Next Article in Journal
Acute Oxidative Stress Can Paradoxically Suppress Human NRF2 Protein Synthesis by Inhibiting Global Protein Translation
Previous Article in Journal
Antioxidant Interactions between Citrus Fruit Carotenoids and Ascorbic Acid in New Models of Animal Cell Membranes
Previous Article in Special Issue
Development and Recovery of Liver Injury in Piglets by Incremental Injection of LPS
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antioxidants
Volume 12
Issue 9
10.3390/antiox12091734
antioxidants-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer

by
Layla Simón
1,2,*,†,
Migdalia Arazo-Rusindo
3,†,
Andrew F. G. Quest
2,4 and
María Salomé Mariotti-Celis
1,*
1
Nutrition and Dietetic School, Facultad de Medicina, Universidad Finis Terrae, Santiago 7501015, Chile
2
Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380000, Chile
3
Department of Chemical and Bioprocess Engineering, Faculty of Engineering, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
4
Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago 8380000, Chile
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Antioxidants 2023, 12(9), 1734; https://doi.org/10.3390/antiox12091734
Submission received: 28 July 2023 / Revised: 31 August 2023 / Accepted: 1 September 2023 / Published: 7 September 2023
(This article belongs to the Special Issue Antioxidants: Sources, Methods, Health Benefits and Industrial Applications)
Browse Figure
Review Reports Versions Notes

Abstract

:
Mitochondrial dysfunction is an interesting therapeutic target to help reduce cancer deaths, and the use of bioactive compounds has emerged as a novel and safe approach to solve this problem. Here, we discuss the information available related to phlorotannins, a type of polyphenol present in brown seaweeds that reportedly functions as antioxidants/pro-oxidants and anti-inflammatory and anti-tumorigenic agents. Specifically, available evidence indicates that dieckol and phloroglucinol promote mitochondrial membrane depolarization and mitochondria-dependent apoptosis. Phlorotannins also reduce pro-tumorigenic, -inflammatory, and -angiogenic signaling mechanisms involving RAS/MAPK/ERK, PI3K/Akt/mTOR, NF-κB, and VEGF. In doing so, they inhibit pathways that favor cancer development and progression. Unfortunately, these compounds are rather labile and, therefore, this review also summarizes approaches permitting the encapsulation of bioactive compounds, like phlorotannins, and their subsequent oral administration as novel and non-invasive therapeutic alternatives for cancer treatment.

1. Introduction

Cancer cells acquire capabilities that enable tumor growth and metastatic dissemination. Metabolic reprogramming is one of the hallmarks of cancer. The increased cell proliferation observed in neoplastic disease is associated with adjustments in the energy metabolism in order to permit accelerated cell growth and division. Cancer cells metabolize glucose to lactate instead of processing the molecule via mitochondrial respiration [1,2]. Although less efficient, this allows cancer cells to obtain energy, as well as intermediate metabolites required to proliferate and metastasize. Specifically, glycolytic metabolites fuel the biosynthesis of nucleosides and amino acids, essential for the synthesis of macromolecules required during proliferation. Moreover, glycolysis has been associated with the activation of signaling pathways involving proteins such as RAS (rat sarcoma virus oncogene), Myc (Myc proto-oncogene), TP53 (tumor protein suppressor p53), and HIF-1α (hypoxia inducible factor 1 subunit alpha), thereby promoting cancer development and progression [1,3,4,5,6,7,8,9,10,11]. Furthermore, cancer cells display mitochondrial DNA mutations which induce mitochondrial dysfunction associated with tumor development, progression, and chemo-resistance. For instance, mutations in mitochondrial NADH dehydrogenase result in reduced activity of the mitochondrial respiratory Complex I and increased formation of reactive oxygen species (ROS), which increase the metastatic potential of murine Lewis lung carcinoma cells [12]. In addition, some mitochondrial DNA mutations increase ROS levels, resulting in increased Akt (also known as protein kinase B, PKB), MAPK (mitogen-activated protein kinase), and HIF-1α-dependent signaling pathways, thereby promoting cancer progression [13,14,15]. Meanwhile, partial depletion of mitochondrial DNA increases anti-apoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-X(L) (B-cell lymphoma-extra-large) protein levels and induces the sequestration of the proapoptotic factors Bid (BH3-interacting domain death agonist), Bax (Bcl-2-like protein 4) and Bad (Bcl-2 associated agonist of cell death) in the inner mitochondrial membrane, thus preventing cell death through apoptosis, which again favors cancer development [16,17].
ROS are generated as byproducts of the mitochondrial electron transport chain and NADPH oxidases. In addition, peroxisomes and endoplasmic reticulum (ER) membranes generate ROS. Mitochondrial ROS are mainly produced by complexes I and III, and while 50% is retained within the mitochondrial matrix, the other 50% is released to the cytoplasm [18]. Subsequently, ROS inhibit the phosphatases PTEN (phosphatase and tensin homolog) and PTP1B (protein tyrosine phosphatase non-receptor type 1), negative regulators of the PI3K/Akt/mTOR and MAPK/ERK mitogenic signaling cascades, thereby driving the survival and proliferation of cancer cells [19,20,21]. Furthermore, ROS promote the epithelial-to-mesenchymal (EMT) transition of cancer cells through cytoskeleton rearrangement induced by Rac1 (Rac family small GTPase 1), RhoA (Ras homolog family member A) and FAK (focal adhesion kinase) [22,23,24]. Moreover, ROS induce NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) phosphorylation, increase matrix metalloproteinase (MMP) expression, and enhance extracellular matrix degradation [25,26]. Also, ROS suppress HIF-1α degradation and induce angiogenesis [27,28,29]. Therefore, ROS increase the metastatic potential of cancer cells. On the other hand, excessive ROS increments have antitumoral effects by inducing cancer cell death [27,30,31,32,33]. In this sense, cancer treatment could be possible by reducing or increasing ROS levels, in order to prevent early neoplasia or to kill cancer cells, respectively [27].
Phytochemicals are secondary plant metabolites with antioxidant properties that play important roles in cancer chemoprevention by reversing oxidative stress-induced malignant transformation. Indeed, populations that consume high levels of plant-derived foods enriched in polyphenols have reduced cancer incidence [34]. In this way, curcumin, epigallocatechin gallate, and resveratrol inhibit cancer cell proliferation, survival, migration, invasion and thereby tumor growth and metastasis [27,35]. Hence, utilizing polyphenols as an orally administered therapeutic alternative represents a less invasive approach [36] to cancer prevention.
Phlorotannins are phenolic compounds produced by sea algae with elevated antioxidant capacity compared to polyphenols from terrestrial plants. They have demonstrated bioactive properties, including the reduction of oxidative stress, inflammation and tumorigenesis. Due to the potential of phlorotannins to reduce cancer development and progression, there is great interest in their biopharmaceutical application [34].
Although phlorotannins possess numerous relevant bioactivities, their therapeutic applications, when orally administrated, are limited due to low bioavailability. The primary factors that affect their bioavailability include low solubility, poor stability, low absorption in the human gastrointestinal tract, extensive biotransformation within the gut, and rapid clearance from the body [37]. In this respect, numerous strategies have been employed to enhance the bioavailability of polyphenols, which seek to overcome their limited absorption and utilization in the body. One approach involves the use of food matrices or delivery systems that can improve the solubility and stability of polyphenols during digestion [36].
Encapsulation techniques, such as microencapsulation, nanoemulsions or nanoparticles and liposomes, among others, have shown promise in enhancing polyphenol bioavailability by protecting them from degradation and promoting their absorption [36]. These strategies are being actively investigated and hold considerable potential for maximizing the therapeutic benefits of polyphenols, including phlorotannins, when administered via oral delivery systems in various health applications.
This review will summarize the available literature related to mitochondrial dysfunction-promoting cancer. In addition, we will discuss the evidence available relating to phlorotannins as antitumoral therapeutic agents targeting mitochondrial dysfunction. Finally, we will highlight the rational design of oral delivery systems for phlorotannins using encapsulation techniques as a novel and non-invasive therapeutic alternative in cancer treatment.

2. Mitochondrial Dysfunction and Oxidative Stress in Cancer

Cancer cells exhibit mitochondrial dysfunction due to defects in tricarboxylic acid (TCA) cycle enzymes and the mitochondrial electron transport chain, mitochondrial DNA mutations, oxidative stress, as well as aberrant oncogene and tumor suppressor signaling [38,39,40,41,42,43,44,45,46]. Subsequently, mitochondrial dysfunction can promote cancer progression to an apoptosis-resistant/chemo-resistant and/or invasive phenotype through various mechanisms involving KRAS, c-Myc, MAPK, AMPK (AMP-activated protein kinase), PI3K/Akt, HIF-1α and TP53 [15,38,47,48,49,50]. Furthermore, oxidative stress, generated as a consequence of the aberrant mitochondrial metabolism, plays a dual role in normal and cancer cells. For instance, the accumulation of ROS is detrimental in normal cells, but cancer cells maintain high levels of metabolism and generate ROS that facilitate the activation of several signaling pathways and promote cancer progression. However, the increase in ROS beyond a certain threshold level becomes toxic and promotes cancer cell death. For that reason, metabolic tumor reprogramming favors glycolysis and mechanisms transforming pyruvate to lactate, which consumes and reduces ROS to non-toxic levels in cancer cells (reviewed in [51]).

3. Phlorotannins, a Group of Bioactive Compounds with Cancer-Preventing Potential

The ROS balance is highly relevant in cancer therapy. Some chemotherapies increase ROS to toxic levels, thereby promoting cancer cell death. Alternatively, antioxidants that reduce ROS content also serve to prevent signaling pathways related to cancer progression (reviewed in [51]). The metabolic reprogramming from oxidative phosphorylation to a glycolytic metabolism results in cells that generate fewer ROS. Consequently, glycolytic cancer cells are resistant to chemotherapeutic agents that rely on the production of ROS and induction of apoptosis [52]. Furthermore, the level of glycolysis correlates with tumor migration, invasion, and metastasis [2], making the targeting of glycolysis, mitochondria and ROS important approaches for the development of novel therapies.
Polyphenols are bioactive compounds widely present in terrestrial and marine plants that display antioxidant and anti-inflammatory properties [53,54,55]. In addition, they have been attributed anti-tumorigenic properties, whereby some bioactive compounds prevent cancer through metabolic control. For instance, novel polyphenols inhibit cell growth, glycolysis, and mitochondrial respiration in colorectal cancer cells. One proposed mechanism is the activation of AMPK signaling and induction of caspase-dependent apoptosis [56]. In addition, oleuropein, the main bioactive phenolic component present in olive leaves, prevents the aerobic glycolysis exploited by tumor cells. This reduction in activity is attributable to a significant decrease in glucose transporter-1, protein kinase isoform M2, and monocarboxylate transporter-4 expression in melanoma, colon carcinoma, breast cancer, as well as chronic myeloid leukemia cells [57].
Marine polyphenols are bioactive compounds obtained from seaweeds. These polyphenols are grouped as phlorotannins, simple phenolic acids, flavonoids, and bromophenols. Marine polyphenols indeed possess antioxidant capacity and have demonstrated enzyme inhibitory, antimicrobial, antiviral, anticancer, antidiabetic and anti-inflammatory activities [58,59,60,61,62,63,64,65,66]. Phlorotannins are a type of marine polyphenol found exclusively in high levels in brown seaweeds. They are phloroglucinol polymers and exhibit superior antioxidant capacity compared to the other families of phenolic compounds [67]. Phlorotannins are classified according to their chemical structure as fucols, phlorethols, fucophlorethols, fuhalols, carmalols and eckols [58,68].
For decades, researchers have extracted phlorotannins from brown seaweeds to study their biological properties. Indeed, the ability of phlorotannins to reduce the development and progression of cancer has been evaluated in different models.
For instance, extracts obtained from Ecklonia stolonifera have been probed in hepatocellular cancer cells. There, 100 µM dieckol, a type of phlorotannin enriched in Ecklonia stolonifera extracts, increases cytochrome c release and induces apoptosis in Hep3B and Sk-Hep1 liver cancer cells through Bid and caspase-3, 7, 8, and 9-dependent mechanisms (Table 1) [69]. Commercially available dieckol (34 and 67 µM) promotes cell death through the activation of the caspases-3, 8, and 9 in A549 non-small-cell lung cancer cells. Moreover, dieckol reduces migration and invasion of lung cancer cells by decreasing matrix metalloproteinase-9 (MMP-9) and increasing E-cadherin levels. In addition, the PI3K/Akt signaling pathway is downregulated by dieckol, thereby affecting lung cancer cell survival, proliferation, and metastatic potential [70].
Another protein relevant to the migration and invasion of cancer cells is HIF-1α, which is increased in cancer and hypoxic conditions. In fact, hypoxia promotes HIF-1α expression, ROS generation, migration and invasion of HT29 colon cancer cells [71]. Like other phlorotannins that are known to be antioxidants [72], Ecklonia cava-isolated dieckol (34 mM) also reduces hypoxia-induced HIF-1α and ROS levels, as well as increases E-cadherin expression, thereby inhibiting migration and invasion [71]. Moreover, Ecklonia cava-isolated dieckol at a lower concentration (34 µM) attenuates ROS-induced increases in MMP-9 levels, as well as FAK and Rac1 activation, thereby preventing the ROS-enhanced migration and invasion of HT1080 fibrosarcoma [73], as well as B16F10 melanoma cells [74].
In a rat model of N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis, the oral administration of Ecklonia cava-isolated dieckol prevents lipid peroxidation, as well as liver cell damage and promotes the enzymatic and non-enzymatic antioxidant defense system, thereby preventing hepatocarcinogenesis in vivo. In this rat model, Ecklonia cava-isolated dieckol and the carcinogenic drug NDEA were administrated simultaneously during 15 weeks. In these experiments, 10 and 20 mg/kg body weight of dieckol administrated orally were observed to have less cancer-preventive effects than 40 mg/kg b.w. of dieckol, revealing thereby dose- and concentration-dependent effects in preventing cancer initiation [75]. The mechanisms proposed are the induction of apoptosis via the intrinsic pathway by decreasing Bcl-2 expression and increasing the expression of Bax, favoring cytochrome c release and caspase-9/3 activation. Moreover, dieckol, present in extracts, reduces VEGF levels, thereby inhibiting angiogenesis. In addition, dieckol inhibits the pro-inflammatory transcription factor NF-κB, as well as reducing COX2 (cyclooxygenase 2) levels in a NDEA-induced hepatocarcinogenesis model [76].
Additionally, in vivo anticarcinogenic effects of eckol, another natural phlorotannin derived from marine brown algae, are reportedly linked to their ability to modulate the immune response in mice with sarcoma. In a mouse model of transplanted sarcoma, eckol derived from brown algae increases TUNEL-positive apoptotic cells via caspase-9/3 activation and down-regulates the expression of Bcl-2, Bax, and EGFR (epidermal growth factor receptor), as well as EGFR phosphorylation. In this xenograft-bearing mouse model, eckol was orally administrated as a pre-treatment for 7 days. Then, tumor cells were subcutaneously implanted and eckol was continuously administrated for another 10 days. Following this protocol, 0.25 and 0.50 mg/kg body weight of eckol administrated orally were found to have less cancer-preventive effects than 1 mg/kg b.w. of eckol, thereby revealing dose- and concentration-dependent effects in preventing cancer promotion [77].
As mentioned before, cancer cells undergo metabolic reprogramming by increasing glycolysis to replace mitochondrial metabolism. In this way, cancer cells control ROS levels, providing sufficient conditions to activate favorable signaling pathways without inducing apoptosis. A novel phloroglucinol quinone was identified that targets both cancer cells that depend on glycolytic pathways or mitochondrial metabolism, albeit through different mechanisms. On the one hand, 50 µM phloroglucinol quinone induces mitochondrial membrane depolarization and loss of mitochondria electron transport, thereby reducing ATP synthesis and affecting HL-60 and HeLa cancer cells that maintain basal levels of mitochondrial metabolism. On the other hand, phloroglucinol prevents autophagy and reduces nutrient recycling, thereby affecting glycolytic cancer cells [52].
Other synthetic phloroglucinols, hyperforin and myrtucommulone A acylphloroglucinols, have been shown to reduce HL-60 leukemia cell viability by directly affecting mitochondria at 0.03–0.9 µM. These phloroglucinols act as protonophores that dissipate the mitochondrial membrane potential, eliminate the mitochondrial proton motive force, and reduce ATP synthesis, which in turn activates AMPK and the intrinsic apoptosis pathway [78]. These effects were reviewed previously, showing that phloroglucinol has the ability to prevent cancer development and progression through the inhibition of mitochondrial metabolism and ROS production as well as inflammatory, angiogenic, and metastatic pathways [79,80,81,82].
Fucus vesiculosus-derived phlorotannin extracts exert specific cytotoxicity against Caco-2 and HT29 colon and MKN-28 gastric tumor cells without affecting the viability of HFF-1 normal cells. Specifically, eckstolonol and fucofurodiphlorethol, between 0.4 and 2.4 mM phloroglucinol equivalent, induce cell cycle arrest and apoptosis in cancer cells [83]. In addition, 1% phlorotannin-rich extracts derived from the brown algae Ascophyllum nodosum and Fucus vesiculosus have been shown to reduce ROS levels, thereby preventing cancer progression in A549 lung cancer cells [84].
On the other hand, phlorotannins have also been described as bioactive compounds that prevent cancer progression by increasing oxidative stress. Commercially available dieckol induces ROS generation and apoptosis in MG-63 human osteosarcoma cells through the activation of caspase-3 and the inhibition of the PI3K/Akt/mTOR signaling pathway. Also, 15 µM of commercially available dieckol reduces metalloproteinase levels and inflammatory markers (TNF (tumor necrosis factor), NF-κB, COX2, and IL-6 (interleukine-6)) [85], indicative of anti-metastatic and anti-inflammatory effects.
Moreover, 400 µg/mL Ecklonia maxima and Ulva rigida extracts induce apoptosis in HepG2 liver cancer cells through inhibition of the mitochondrial membrane potential and increasing ROS [86]. Also, Ecklonia cava extracts enriched in dieckol have cytotoxic effects in ovarian cancer cells and reduce tumor growth in xenograft mouse models when administrated orally at 100 mg/kg b.w. during 4 weeks. In vitro, 120 µM dieckol isolated from Ecklonia cava induces apoptosis in SKOV3 ovarian cancer cells through the activation of caspase-8,-9 and -3, as well as by inhibiting the Akt signaling pathway. At the mitochondrial level, dieckol induces mitochondrial membrane depolarization and cytochrome c release, as well as increases the expression of pro-apoptotic proteins. Additionally, dieckol downregulates the expression of anti-apoptotic proteins, such as XIAP (X-linked inhibitor of apoptosis protein), FLIP ((FADD-like IL-1β-converting enzyme)-inhibitor protein), and Bcl-2, thereby promoting apoptosis. These effects are associated with ROS increments. Indeed, the antioxidant N-acetyl-L-cysteine prevents caspase activation, cytochrome c release, Bcl-2 downregulation, and apoptosis that are caused by exposure to the seaweed extract [87].
Additionally, phlorotannins also improve the effects of chemotherapy by promoting apoptosis in cancer cells while protecting normal cells. Indeed, the combined administration of phlorotannin (dieckol)-rich extracts of Ecklonia cava and cisplatin potentiates the effects of each drug administrated alone by inducing apoptosis via the increase in ROS and inhibition of the Akt/NF-κB pathway. Moreover, dieckol-rich extracts suppress cisplatin-induced normal kidney cell damage [88].
Table 1. Phlorotannins preventing cancer development and progression.
Table 1. Phlorotannins preventing cancer development and progression.
Bioactive CompoundModel DosisREDOX
Balance		MechanismDiseaseReference
Dieckol, isolated from Ecklonia stoloniferaHepatocellular carcinoma (Hep3B and Sk-Hep1) cells
100 µM, 24 h		AntioxidantRelease of cytochrome c from mitochondria and induction of apoptosisHepatocellular carcinoma[69]
DieckolNon-small-cell lung carcinoma A549 cell line
25 and 50 µg/mL (34 and 67 µM), 24 h		AntioxidantInduction of apoptosis through caspases-3, 8, and 9. Inhibition of proliferation and migration by regulating the PI3K/AKT signaling pathwayNon-small-cell lung cancer[70]
DieckolHT29 cells
25 mg/mL (34 mM), 3 and 12 h		AntioxidantInhibition of HIF-1α, ROS, migration, and invasionColon cancer[71]
Dieckol, isolated from Ecklonia cavaHT1080 cells
25 µg/mL (34 µM), 24 and 48 h		AntioxidantReduction of ROS, Rac1, FAK, adhesion, migration, and invasionFibrosarcoma[73]
Dieckol, isolated from Ecklonia cavaB16F10 cells
25 µg/mL (34 µM), 24 and 48 h		AntioxidantReduction of NADPH oxidase, ROS, Rac1, migration, and invasionMelanoma[74]
Dieckol, isolated from Ecklonia cavaRat model of NDEA-induced hepatocarcinogenesis
40 mg/kg, 15 weeks, oral		AntioxidantIncrement of antioxidant enzymes, thereby preventing hepatocarcinogenesis in vivoHepatocarcinoma[75]
Dieckol, isolated from Ecklonia cavaRat model of NDEA-induced hepatocarcinogenesis
40 mg/kg, 15 weeks, oral		AntioxidantInduction of mitochondria-dependent apoptosis: decreased Bcl-2 and increased Bax, cytochrome c release, and caspase-3 activation. Promotion of inflammation and angiogenesis via NF-κB, COX2, and VEGF. Hepatocarcinoma[76]
EckolXenograft-bearing mice
1 mg/kg, pretreatment for 7 days + treatment 10 days, oral		AntioxidantIncreased TUNEL-positive apoptotic cells, increased caspase-3
and caspase-9 activation, and reduced expression of Bcl-2, EGFR and EGFR phosphorylation
Stimulation of innate and adaptive immune responses		Sarcoma[77]
Phloroglucinol, quinone PMT7HL-60, HeLa, K562, and T98G cells
50 µM, 90 min, 24, 48 and 72 h		AntioxidantMitochondrial membrane depolarization and inhibition of autophagyLeukemia, cervical carcinoma, and glioblastoma[52]
Acylphloroglucinols, hyperforin, and myrtucommulone AHL-60 cells
EC50 0.03–0.9 µM		AntioxidantMitochondrial membrane depolarization and induction of apoptosisLeukemia[78]
Eckstolonol and fucofurodiphlorethol, derived from Fucus vesiculosusCaco-2, HT29, MKN-28, and HFF-1 cells
50–300 µg/mL (0.4–2.4 mM phloroglucinol equivalent), 48 h		AntioxidantInduction of cell cycle arrest and apoptosisColon and gastric cancer[83]
Phlorotannin-rich extract from Ascophyllum nodosum and Fucus vesiculosusA549 cells
1% extracts, 20 min preincubation		AntioxidantReduction of ROSLung cancer[84]
Commercial dieckolMG-63 cells
15/20 µM, 24 h		Pro-oxidantInduction of ROS generation and apoptosis
Inhibition of PI3K/AKT/mTOR pathway
Reduction of TNF-α, NF-κB, COX2, IL-6, and matrix metalloproteinase levels		Sarcoma[85]
Extracts from Ecklonia maxima and Ulva rigidaHepG2 cells
200 and 400 µg/mL extracts, 48 h		Pro-oxidantReduction of mitochondrial membrane potential. Increment of ROS. Induction of apoptosis.Liver cancer[86]
Dieckol isolated from Ecklonia cavaSKOV3 cells
60–120 µM, 24 h
SKOV3 xenograft mice model
100 mg/kg, 4 weeks, oral		Pro-oxidantInduction of apoptosis in cancer cells (mitochondrial membrane depolarization, activation of caspases), thereby reducing cancer cell viability and tumor xenograft growth through the increment of ROSOvarian cancer[87]
Dieckol-rich extract of Ecklonia cava and cisplatinSKOV3 cells
100 µg/mL (800 µM), 24 h
SKOV3 xenograft mouse model
100 mg/kg, 4 weeks, oral		Pro-oxidantInduction of ROS and apoptosis.
Inhibition of NF-κB and Akt signaling.		Ovarian cancer[88]
Based on the aforementioned evidence, commercial and seaweed-isolated phlorotannins are effective at preventing cancer development and progression. In vitro results show potential anti-tumorigenic effects in a wide range of concentrations (15 µM–34 mM). Moreover, pre-clinical experiments demonstrate that dieckol isolated from Ecklonia cava reduces cancer initiation and development at 40 and 100 mg/kg b.w. in rats and mice, respectively. In addition, the pre-treatment with lower doses of eckol (1 mg/kg b.w.) prevents cancer promotion in xenograft-bearing mice.

4. Delivery Strategies Applied to Phlorotannin Encapsulation

Traditional cancer therapies are invasive, often ineffective due to the development of drug resistance, non-targeted delivery, and adverse side effects. These factors have increased the focus on bioactive phytochemicals as potential alternatives for the treatment of cancer. Information provided in the previous section would indicate that phlorotannins have emerged as powerful chemo-preventive and chemo-protective compounds, as they can promote apoptotic cell death both in vitro and in vivo [89].
Despite the multiple health benefits, the application of phlorotannins is challenging, specifically when they are administered orally. The biological activity of these polyphenols is limited mainly by their lack of solubility and permeability, as well as their extensive biotransformation by the gut microbiota, which determines their degree of absorption in the human gastrointestinal tract (GIT) [90,91]. Therefore, the effectivity of phlorotannins is determined by their bioaccessibility and bioavailability, since they need to be properly digested and absorbed in order to access the bloodstream and then reach the appropriate target location [37]. For these reasons, several intrinsic and environmental factors affect these molecules (Figure 1). These include long-term storage, manufacturing and transit through the GIT, all of which play significant roles in either enhancing or diminishing the bioactivity of phlorotannins [92]. In fact, in the absence of appropriate protection, phlorotannins are susceptible to transformation and metabolic processing which render them inactive. Thus, in order to benefit from these biomolecules, stabilization of phlorotannins is essential [93].
Various delivery strategies are currently under investigation to enhance the bioaccessibility and bioavailability of phlorotannins. These approaches aim to facilitate the development of novel biopharmaceutical applications involving brown seaweed as a natural resource of phlorotannins [94,95].
Encapsulation is the most common technique and consists of “packaging” the core material with functional activity (phlorotannin) into a polymer matrix or coating material (encapsulant) to form a capsule system (oral delivery system) [96]. The main actions of this technology currently focus on
  • Protecting the phlorotannins from degradation by environmental factors during their storage (light, oxygen, extreme pH, high temperature, etc.) and gastrointestinal passage [93].
  • Avoiding unfavorable interactions between phlorotannins and other components of food, nutraceuticals or pharmaceutical matrices, such as proteins, lipids or complex carbohydrate macromolecules [97].
  • Masking the unpleasant organoleptic properties of the phlorotannin extracts [98].
The different techniques that can be used to elaborate phlorotannin capsule systems can be divided into physical, chemical, and physicochemical methods (Table 2) [99]. The application of physical processes during encapsulation generally involves dehydration or cooling techniques. In the application of chemical methods, the encapsulating matrix components either undergo chemical reactions between themselves or with the bioactive agent. Physicochemical methods combine chemical interactions with physical processes to form the encapsulating matrix. With these systems, it is possible to control the release of orally administered phlorotannins at the target site, as well as modulate their bioaccesibility and therefore their bioavailability (Table 2). The growing industrial interest in using phlorotannins in pharmaceutical applications has increased efforts to improve their bioaccessibility/bioavailability by designing specific delivery platforms. Nevertheless, compared to phenolic compounds from terrestrial plants, research focused on phlorotannin encapsulation from seaweed is still relatively scarce. For many years, drying techniques have been used to encapsulate different compounds due to their low costs, simple operation and flexibility. Two main drying techniques are used for encapsulation: spray-drying and freeze-drying [99]. Spray-drying was used by Cuong et al. [100] and Nkurunziza et al. [101] for powder preparations of phlorotannin extracts from brown algae. Cuong et al. [100] studied the impact of different spray-drying conditions (flow rate, inlet/outlet temperature, polymer/bioactive relation, and pressure) on phlorotannin content and antioxidant activity of a nano phlorotannin powder prepared from the brown algae Sargassum serratum. Under optimal conditions, the antioxidant activity of the encapsulated phlorotannin extract reached the highest values for the total antioxidant reducing power and DPPH free radical scavenging (4.347 ± 0.018 g ascorbic acid equivalent/100–1 g, 9.390 ± 0.024 g FeSO4 equivalent 100–1 g, and 70.02 ± 0.26%, respectively). Different powders of encapsulated brown algae extract from Saccharina japonica were prepared through spray-drying encapsulation with different encapsulant polymers (dextrin, maltodextrin, lactose, Arabic gum, whey protein isolate, gelatin, and sodium caseinate). The antioxidant activities (DPPH and ABTS assays) of the powders were higher than for the protein-coated materials compared with when polysaccharides were used [101].
Freeze-drying techniques can improve the stability of phlorotannins by preventing their degradation at high temperatures, as in the spray-drying and oven methods. Anwar et al. [102] prepared a powder of brown seaweed (Sargassum plagyophyllum) extract with a maltodextrin dextrose equivalent 10–15 units using a freeze-drying method. The powder formulations significantly improved the stability of phlorotannins during the drying process, but the IC50 (DPPH assay) could not be calculated since the percentage inhibition did not reach 50%.
Lipid-based delivery systems, such as emulsions/nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and liposomes are the techniques widely used to increase the solubility, stability, bioaccessibility and bioavailability of various phenolic compounds [103]. Especially liposomes are well-suited for increasing the stability of phenolic compounds by protecting them from extreme pH, temperatures, and ion concentrations [104].
Liposomes are vesicles consisting of single or multiple bilayers composed of phospholipids, which have one hydrophilic head and two hydrophobic fatty acid tails. Consequently, the biphasic character of liposomes allows the entrapment of hydrophilic, lipophilic and amphiphilic molecules [103]. The interactions between phlorotannins and liposome-based systems have been demonstrated to be an effective strategy for cancer treatment thanks to the site-specific delivery of phenolic compounds [105]. The use of folate-conjugated, PEGylated nanoliposomes for encapsulating a polyphenolic-rich extract from Kappaphycus alvarezii increases the cellular uptake efficiency of the bioactive compounds, and thus inhibits the growth and induces the apoptosis of human adenoma MCF-7 breast cancer cells [105].
Further, the antioxidant activity (DPPH, ABTS, and FRAP assays) of nanoliposomes for encapsulation of Sargassum boveanum extract was evaluated, showing a controlled release of phenolic compounds at different pH values, whereby the burst in release was observed at pH = 3. The antioxidant capacity of nanoliposomes was lower than for free algae extracts, which could be because a large proportion of the phenolic compounds are inside the core of nanoliposomes [106]. Subsequently, the same liposome-based systems were used as functional ingredients for developing a mayonnaise with antioxidant and antimicrobial properties. The different formulations of mayonnaise prepared with the nanoliposomes not only improved the antimicrobial potential of Sargassum boveanum extract against P. aeruginosa, E. coli, and B. cereus but also masked the strong taste and color of extracts, as well as increased the oxidative stability of mayonnaise [106].
Aqueous seaweed extracts from Sargassum incisifolium were used for the green synthesis of silver and gold nanoparticles, and their potential as antimicrobial and cytotoxic agents was investigated by Mmola et al. [107]. They observed that silver nanoparticles were toxic to Gram-negative bacteria, while the gold nanoparticles lacked such activity. Likewise, the normal human breast cell line MCF-12a was found to be resistant to the silver nanoparticles, while the colon cancer cell line HT-29 was more sensitive (10% viability). The gold nanoparticles displayed negligible toxicity.
Depending on the material used for their fabrication and the preparation technique, these systems can differ in terms of size and morphology. Based on the size, the encapsulated particles could be classified as nanocapsules (<0.2 μm), microcapsules (0.2–5000 μm) or macrocapsules (>5000 μm) [108,109]. Regardless of their size and distribution, particles can have different morphologies depending on the materials (active component and encapsulant) and the technique used in their preparation. According to Yoshizawa [110], the morphology of the particles or capsules can be categorized as single or mono-core, multi or poly-core and matrix type.
Table 2. Different technologies applied to phlorotannin encapsulation.
Table 2. Different technologies applied to phlorotannin encapsulation.
MethodTechniqueBioactive CompoundCoating MaterialReference
Physical encapsulationSpray-dryingPhlorotannin extract
(Sargassum serratum)		Maltodextrin, glucose, and saccharose[100]
Freeze-driedPhlorotannin extract
(Sargassum plagyophyllum)		Maltodextrin[102]
Chemical encapsulationComplexationPhlorotannin extracts
(Eisenia bicyclis, Ecklonia cava and Ecklonia kurome)		Soybean protein isolate[111]
Phlorotannin extract
(Laminaria digitata)		β-casein (random coil) and bovine serum albumin (globular)[112]
Phlorotannins (80% purity)Polyvinylpyrrolidone nanoparticles[113]
Phlorotannin extracts
(Undaria pinnatifida)		Myofibrillar protein from Scomberomorus niphonius [114]
EmulsionPhlorotannin extract
(Sargassum fusiforme)		Propylene glycol and glycerol[115]
LiposomesPhlorotannin extract
(Sargassum boveanum)		Soybean lecithin and glycerol[106]
Phlorotannin extract
(Kappaphycus alvarezii)		Folic acid-PEG-DSPE conjugate[105]
Physiochemical encapsulationSpray-drying/
emulsion		Phlorotannin extract
(Saccharina japonica)		Polysaccharides (dextrin, maltodextrin, lactose and gum arabic)
Proteins (whey protein isolate, gelatin and sodium caseinate)		[101]
Freeze-dried/
complexation		Phlorotannin extract
(Sargassum incisifolium)		Gold (III) chloride tryhidrate and silver nitrate (AgNO3)[107]
Phlorotannin extract
(Ecklonia cava)		Silver nitrate (AgNO3)[116]
Phlorotannin extract
(Sargassum ilicifolium)		Chitosan and tripolyphos-phate (TPP)[95]
ElectrospinningPhlorotannin (Zhengzhou Bainafo Bioengineering Co., Ltd., Zhengzhou, Henan, China)Polyethylene oxide and sodium alginate[117]
Phlorotannin (purchased from Zhengzhou Bainafo Bioengineering Co., Ltd., Zhengzhou, Henan, China)Momordica charantia polysaccharide[118]

5. Essential Variables to Modulate the Bioaccessibility and Bioavailability of Phlorotannin Capsule Systems

The design of an effective oral delivery system involving the encapsulation of phlorotannins must consider several variables that play a key role in influencing the interactions between the carriers and the biological interface in the GIT. It is essential to select encapsulants that are suitable for the specific pH conditions in each segment of the GIT and are also compatible with GIT enzymes and gut microbiota. Furthermore, various physicochemical properties of particles, such as size, shape, and surface properties, have been shown to determine the bioaccessibility of phlorotannin capsule systems.

5.1. Composition and Chemical Nature of the Encapsulants

The nature and chemical composition of the encapsulants, including polysaccharide/protein complexes or polysaccharide/protein/lipid systems with different concentrations and polymer ratios, can influence phlorotannin bioaccesibility. Together, these inherent characteristics determine the behavior, interactions and performance of the encapsulant during gastrointestinal passage. According to Cassani et al. [93], the complexes formed between polyphenols and carbohydrates or proteins are poorly digested in the upper intestinal tract because of steric hindrance. They reach the colon almost unaltered, where they serve as substrates for the microbial community, resulting in readily absorbable metabolites. O’Sullivan et al. [119] demonstrated that the antioxidant activity of phlorotannin-rich milk samples (DPPH radical scavenging assay) remained stable after a simulated in vitro digestion. It was suggested that the passage of phlorotannins through the GIT should not be affected by interactions with other milk components, such as whey protein isolate, casein and fat. Soybean proteins have also been used to form complexes with phlorotannins extracted from Eisenia bicyclis, Ecklonia cava and Ecklonia kurome. These phlorotannin-soybean protein complexes may be useful as a novel functional foodstuff or supplement with higher DPPH-radical scavenging activity than soybean protein [111].
Moreover, alginate, a natural polysaccharide of brown seaweeds, is resistant to digestion by human enzymes, but can be digested by the human gut microbiota [120]. Conversely, chitosan, a linear polysaccharide derived from chitin, can be partially digested by human enzymes [121]. Thus, through the careful selection of appropriate encapsulants, it becomes feasible to effectively regulate the release of bioactive components from the delivery system precisely at the intended target site.

5.2. Physicochemical Properties of Capsule Systems

The physicochemical properties of capsule systems include a range of characteristics, such as size, shape and surface properties. These properties affect various aspects of the encapsulated bioactive compounds, such as their stability, release kinetics and interaction with biological systems [122]. Overall, by carefully considering and optimizing the physicochemical properties of capsules, it is possible to enhance the encapsulation efficiency (EE) of bioactive compounds (EE is defined as the experimental loading/theoretical loading × 100%). This, in turn, leads to more efficient and effective delivery systems. As a reference, effective drug delivery systems usually require an EE to be higher than 60% [37].
The particle size and shape of capsule systems can determine the bio-distribution, cytotoxicity and accumulation of the therapeutic agents in the GIT and/or in the blood stream. Particle size is a critical parameter that affects the behavior of capsule systems because it determines bioavailability, absorption and distribution within the body. Smaller particles tend to result in improved cellular uptake and higher surface area-to-volume ratios, facilitating efficient interactions with target cells or tissues. Furthermore, the shape of the capsule systems can influence their behavior, including their circulation time in the body and interactions with biological barriers [123,124].
The surface charges of delivery systems play a significant role in the stability, dispersibility and effectiveness of oral administration [125]. The surface charges are modified using cationic or anionic polysaccharides, such as chitosan or alginate, respectively. Negatively charged particles are trapped by cells of the immune system and diffuse 20 to 30 times faster through the mucous layer than positively charged particles. In contrast, positively charged particles adhere to the mucin of the epithelium [126]. Therefore, a balance between the mucoadhesive and diffusion properties is important for the efficient bioactive release into the mucosa [127]. Consequently, the surface chemistry of the delivery systems defines their biocompatibility, biodistribution, as well as clearance and therefore their bioavailability [124,125].

6. Conclusions

In conclusion, cancer occurrence and progression are associated with metabolic reprogramming, increased glycolysis, mitochondrial dysfunction, and ROS production that activate several signaling pathways, thereby promoting proliferation, survival, migration, invasion, and metastasis. On the other hand, phlorotannins reduce cancer development by inhibiting ROS production and the signaling pathways described above. In addition, phlorotannins may prevent cancer through the increment of ROS levels and mitochondrial-dependent apoptosis. In this manner, phlorotannins appear as novel and non-invasive therapeutic alternatives for cancer treatment, but because of their chemical characteristics, their encapsulation for oral administration is required.

Author Contributions

Conceptualization, L.S., M.A.-R. and M.S.M.-C.; investigation, L.S. and M.A.-R.; writing—original draft preparation, L.S. and M.A.-R.; writing—review and editing, L.S., M.A.-R., A.F.G.Q. and M.S.M.-C.; funding acquisition, L.S., A.F.G.Q. and M.S.M.-C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by FONDECYT regular grant 1210644, FONDAP 15130011 (A.F.G.Q.), FONDECYT iniciación 11230112 (L.S.), Concurso de Investigación con Colaboración Internacional de la Universidad Finis Terrae (L.S.), and FONDECYT regular grant 1220097 (M.S.M.-C.).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef]
  2. Díaz-Valdivia, N.; Simón, L.; Díaz, J.; Martinez-Meza, S.; Contreras, P.; Burgos-Ravanal, R.; Pérez, V.I.; Frei, B.; Leyton, L.; Quest, A.F.G. Mitochondrial Dysfunction and the Glycolytic Switch Induced by Caveolin-1 Phosphorylation Promote Cancer Cell Migration, Invasion, and Metastasis. Cancers 2022, 14, 2862. [Google Scholar] [CrossRef] [PubMed]
  3. McGrail, K.; Granado-Martínez, P.; Esteve-Puig, R.; García-Ortega, S.; Ding, Y.; Sánchez-Redondo, S.; Ferrer, B.; Hernandez-Losa, J.; Canals, F.; Manzano, A.; et al. BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy. Nat. Commun. 2022, 13, 7113. [Google Scholar] [CrossRef] [PubMed]
  4. Amendola, C.R.; Mahaffey, J.P.; Parker, S.J.; Ahearn, I.M.; Chen, W.-C.; Zhou, M.; Court, H.; Shi, J.; Mendoza, S.L.; Morten, M.J.; et al. KRAS4A directly regulates hexokinase 1. Nature 2019, 576, 482–486. [Google Scholar] [CrossRef]
  5. Matoba, S.; Kang, J.-G.; Patino, W.D.; Wragg, A.; Boehm, M.; Gavrilova, O.; Hurley, P.J.; Bunz, F.; Hwang, P.M. p53 regulates mitochondrial respiration. Science 2006, 312, 1650–1653. [Google Scholar] [CrossRef] [PubMed]
  6. Kumagai, S.; Koyama, S.; Itahashi, K.; Tanegashima, T.; Lin, Y.-T.; Togashi, Y.; Kamada, T.; Irie, T.; Okumura, G.; Kono, H.; et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022, 40, 201–218.e9. [Google Scholar] [CrossRef] [PubMed]
  7. Shin, N.; Lee, H.; Sim, D.Y.; Im, E.; Park, J.E.; Park, W.Y.; Cho, A.R.; Shim, B.S.; Kim, S. Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c-Myc signaling. Phytother. Res. 2021, 35, 3812–3820. [Google Scholar] [CrossRef] [PubMed]
  8. Kim, J.; Yu, L.; Chen, W.; Xu, Y.; Wu, M.; Todorova, D.; Tang, Q.; Feng, B.; Jiang, L.; He, J.; et al. Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation. Cancer Cell 2019, 35, 191–203.e8. [Google Scholar] [CrossRef] [PubMed]
  9. Roche, M.E.; Ko, Y.; Domingo-Vidal, M.; Lin, Z.; Whitaker-Menezes, D.; Birbe, R.C.; Tuluc, M.; Győrffy, B.; Caro, J.; Philp, N.J.; et al. TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 drive metabolic reprogramming with c-MYC and NFκB activation in breast cancer. Int. J. Cancer 2023. [Google Scholar] [CrossRef] [PubMed]
  10. Wang, J.-Z.; Zhu, W.; Han, J.; Yang, X.; Zhou, R.; Lu, H.; Yu, H.; Yuan, W.; Li, P.; Tao, J.; et al. The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun. 2021, 41, 560–575. [Google Scholar] [CrossRef] [PubMed]
  11. Dong, S.; Liang, S.; Cheng, Z.; Zhang, X.; Luo, L.; Li, L.; Zhang, W.; Li, S.; Xu, Q.; Zhong, M.; et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2022, 41, 15. [Google Scholar] [CrossRef]
  12. Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J.-I. ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis. Science 2008, 320, 661–664. [Google Scholar] [CrossRef] [PubMed]
  13. Park, J.S.; Sharma, L.K.; Li, H.; Xiang, R.; Holstein, D.; Wu, J.; Lechleiter, J.; Naylor, S.L.; Deng, J.J.; Lu, J.; et al. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum. Mol. Genet. 2009, 18, 1578–1589. [Google Scholar] [CrossRef] [PubMed]
  14. Sharma, L.K.; Fang, H.; Liu, J.; Vartak, R.; Deng, J.; Bai, Y. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum. Mol. Genet. 2011, 20, 4605–4616. [Google Scholar] [CrossRef] [PubMed]
  15. Pelicano, H.; Xu, R.-H.; Du, M.; Feng, L.; Sasaki, R.; Carew, J.S.; Hu, Y.; Ramdas, L.; Hu, L.; Keating, M.J.; et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 2006, 175, 913–923. [Google Scholar] [CrossRef]
  16. Guerra, F.; Arbini, A.A.; Moro, L. Mitochondria and cancer chemoresistance. Biochim. Biophys. Acta (BBA) Bioenerg. 2017, 1858, 686–699. [Google Scholar] [CrossRef] [PubMed]
  17. Biswas, G.; Anandatheerthavarada, H.K.; Avadhani, N.G. Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes. Cell Death Differ. 2005, 12, 266–278. [Google Scholar] [CrossRef] [PubMed]
  18. Muller, F.L.; Liu, Y.; Van Remmen, H. Complex III Releases Superoxide to Both Sides of the Inner Mitochondrial Membrane. J. Biol. Chem. 2004, 279, 49064–49073. [Google Scholar] [CrossRef]
  19. Lee, S.-R.; Yang, K.-S.; Kwon, J.; Lee, C.; Jeong, W.; Rhee, S.G. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 2002, 277, 20336–20342. [Google Scholar] [CrossRef]
  20. Salmeen, A.; Andersen, J.N.; Myers, M.P.; Meng, T.-C.; Hinks, J.A.; Tonks, N.K.; Barford, D. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 2003, 423, 769–773. [Google Scholar] [CrossRef] [PubMed]
  21. Calvo-Ochoa, E.; Sánchez-Alegría, K.; Gómez-Inclán, C.; Ferrera, P.; Arias, C. Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production. Neurochem. Int. 2017, 110, 75–83. [Google Scholar] [CrossRef] [PubMed]
  22. Moldovan, L.; Irani, K.; Moldovan, N.I.; Finkel, T.; Goldschmidt-Clermont, P.J. The actin cytoskeleton reorganization induced by Rac1 requires the production of superoxide. Antioxid. Redox Signal 2003, 1, 29–43. [Google Scholar] [CrossRef] [PubMed]
  23. Chiarugi, P.; Pani, G.; Giannoni, E.; Taddei, L.; Colavitti, R.; Raugei, G.; Symons, M.; Borrello, S.; Galeotti, T.; Ramponi, G. Reactive oxygen species as essential mediators of cell adhesion: The oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J. Cell Biol. 2003, 161, 933–944. [Google Scholar] [CrossRef] [PubMed]
  24. Nimnual, A.S.; Taylor, L.J.; Bar-Sagi, D. Redox-dependent downregulation of Rho by Rac. Nat. Cell Biol. 2003, 5, 236–241. [Google Scholar] [CrossRef] [PubMed]
  25. Del Carlo, M.; Schwartz, D.; Erickson, E.A.; Loeser, R.F. Endogenous production of reactive oxygen species is required for stimulation of human articular chondrocyte matrix metalloproteinase production by fibronectin fragments. Free Radic. Biol. Med. 2009, 42, 1350–1358. [Google Scholar] [CrossRef] [PubMed]
  26. Binker, M.G.; Binker-Cosen, A.A.; Richards, D.; Oliver, B.; Cosen-Binker, L.I. EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2. Biochem. Biophys. Res. Commun. 2009, 379, 445–450. [Google Scholar] [CrossRef] [PubMed]
  27. Wang, Y.; Qi, H.; Liu, Y.; Duan, C.; Liu, X.; Xia, T.; Chen, D.; Piao, H.-L.; Liu, H.-X. The double-edged roles of ROS in cancer prevention and therapy. Theranostics 2021, 11, 4839–4857. [Google Scholar] [CrossRef] [PubMed]
  28. Huang, C.; Han, Y.; Wang, Y.; Sun, X.; Yan, S.; Yeh, E.T.H.; Chen, Y.; Cang, H.; Li, H.; Shi, G.; et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J. 2009, 28, 2748–2762. [Google Scholar] [CrossRef] [PubMed]
  29. Gerald, D.; Berra, E.; Frapart, Y.M.; Chan, D.A.; Giaccia, A.J.; Mansuy, D.; Pouysségur, J.; Yaniv, M.; Mechta-Grigoriou, F. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004, 118, 781–794. [Google Scholar] [CrossRef] [PubMed]
  30. Zuo, Y.; Xiang, B.; Yang, J.; Sun, X.; Wang, Y.; Cang, H.; Yi, J. Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1. Cell Res. 2009, 19, 449–457. [Google Scholar] [CrossRef]
  31. Luanpitpong, S.; Chanvorachote, P.; Nimmannit, U.; Leonard, S.S.; Stehlik, C.; Wang, L.; Rojanasakul, Y. Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination. Biochem. Pharmacol. 2012, 83, 1643–1654. [Google Scholar] [CrossRef] [PubMed]
  32. Luanpitpong, S.; Chanvorachote, P.; Stehlik, C.; Tse, W.; Callery, P.S.; Wang, L.; Rojanasakul, Y. Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells. Mol. Biol. Cell 2013, 24, 858–869. [Google Scholar] [CrossRef] [PubMed]
  33. Li, D.; Ueta, E.; Kimura, T.; Yamamoto, T.; Osaki, T. Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci. 2004, 95, 644–650. [Google Scholar] [CrossRef] [PubMed]
  34. Catarino, M.D.; Amarante, S.J.; Mateus, N.; Silva, A.M.S.; Cardoso, S.M. Brown Algae Phlorotannins: A Marine Alternative to Break the Oxidative Stress, Inflammation and Cancer Network. Foods 2021, 10, 1478. [Google Scholar] [CrossRef] [PubMed]
  35. Sanhueza, S.; Simón, L.; Cifuentes, M.; Quest, A.F.G. The Adipocyte–Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy. Antioxidants 2023, 12, 126. [Google Scholar] [CrossRef]
  36. D’andurain, J.; López, V.; Arazo-Rusindo, M.; Tiscornia, C.; Aicardi, V.; Simón, L.; Mariotti-Celis, M.S. Effect of Curcumin Consumption on Inflammation and Oxidative Stress in Patients on Hemodialysis: A Literature Review. Nutrients 2023, 15, 2239. [Google Scholar] [CrossRef] [PubMed]
  37. Tong, T.; Liu, X.; Yu, C. Extraction and Nano-Sized Delivery Systems for Phlorotannins to Improve Its Bioavailability and Bioactivity. Mar. Drugs 2021, 19, 625. [Google Scholar] [CrossRef] [PubMed]
  38. Luo, Y.; Ma, J.; Lu, W. The Significance of Mitochondrial Dysfunction in Cancer. Int. J. Mol. Sci. 2020, 21, 5598. [Google Scholar] [CrossRef]
  39. Balss, J.; Meyer, J.; Mueller, W.; Korshunov, A.; Hartmann, C.; von Deimling, A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008, 116, 597–602. [Google Scholar] [CrossRef]
  40. Zhang, D.; Wang, W.; Xiang, B.; Li, N.; Huang, S.; Zhou, W.; Sun, Y.; Wang, X.; Ma, J.; Li, G.; et al. Reduced succinate dehydrogenase B expression is associated with growth and de-differentiation of colorectal cancer cells. Tumour Biol. 2013, 34, 2337–2347. [Google Scholar] [CrossRef] [PubMed]
  41. Ha, Y.-S.; Chihara, Y.; Yoon, H.-Y.; Kim, Y.-J.; Kim, T.-H.; Woo, S.H.; Yun, S.-J.; Kim, I.Y.; Hirao, Y.; Kim, W.-J. Downregulation of fumarate hydratase is related to tumorigenesis in sporadic renal cell cancer. Urol. Int. 2013, 90, 233–239. [Google Scholar] [CrossRef] [PubMed]
  42. Hu, J.; Locasale, J.W.; Bielas, J.H.; O’Sullivan, J.; Sheahan, K.; Cantley, L.C.; Heiden, M.G.V.; Vitkup, D. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 2013, 31, 522–529. [Google Scholar] [CrossRef] [PubMed]
  43. Yin, P.-H.; Wu, C.-C.; Lin, J.-C.; Chi, C.-W.; Wei, Y.-H.; Lee, H.-C. Somatic mutations of mitochondrial genome in hepatocellular carcinoma. Mitochondrion 2010, 10, 174–182. [Google Scholar] [CrossRef]
  44. Tseng, L.-M.; Yin, P.-H.; Yang, C.-W.; Tsai, Y.-F.; Hsu, C.-Y.; Chi, C.-W.; Lee, H.-C. Somatic mutations of the mitochondrial genome in human breast cancers. Genes Chromosomes Cancer 2011, 50, 800–811. [Google Scholar] [CrossRef] [PubMed]
  45. Hung, W.-Y.; Wu, C.-W.; Yin, P.-H.; Chang, C.-J.; Li, A.F.-Y.; Chi, C.-W.; Wei, Y.-H.; Lee, H.-C. Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim. Biophys. Acta (BBA) Gen. Subj. 2010, 1800, 264–270. [Google Scholar] [CrossRef] [PubMed]
  46. Hopkins, J.F.; Sabelnykova, V.Y.; Weischenfeldt, J.; Simon, R.; Aguiar, J.A.; Alkallas, R.; Heisler, L.E.; Zhang, J.; Watson, J.D.; Chua, M.L.K.; et al. Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 2017, 8, 656. [Google Scholar] [CrossRef]
  47. Hsu, C.C.; Tseng, L.M.; Lee, H.C. Role of mitochondrial dysfunction in cancer progression. Exp. Biol. Med. 2016, 241, 1281–1295. [Google Scholar] [CrossRef] [PubMed]
  48. Koivunen, P.; Hirsilä, M.; Remes, A.M.; Hassinen, I.E.; Kivirikko, K.I.; Myllyharju, J. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: Possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 2007, 282, 4524–4532. [Google Scholar] [CrossRef] [PubMed]
  49. Kerr, E.M.; Gaude, E.; Turrell, F.K.; Frezza, C.; Martins, C.P. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 2016, 531, 110–113. [Google Scholar] [CrossRef] [PubMed]
  50. Hu, Y.; Lu, W.; Chen, G.; Wang, P.; Chen, Z.; Zhou, Y.; Ogasawara, M.; Trachootham, D.; Feng, L.; Pelicano, H.; et al. K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res. 2012, 22, 399–412. [Google Scholar] [CrossRef]
  51. Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; Lleonart, M.E. Oxidative stress and cancer: An overview. Ageing Res. Rev. 2013, 12, 376–390. [Google Scholar] [CrossRef]
  52. Broadley, K.; Larsen, L.; Herst, P.M.; Smith, R.A.J.; Berridge, M.V.; McConnell, M.J. The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress. J. Cell. Biochem. 2011, 112, 1869–1879. [Google Scholar] [CrossRef] [PubMed]
  53. Apak, R.; Özyürek, M.; Güçlü, K.; Çapano, E. Antioxidant activity/capacity measurement. 1. Classification, physicochemical principles, mechanisms, and electron transfer (ET)-based assays. J. Agric Food Chem. 2016, 64, 997–1027. [Google Scholar] [CrossRef] [PubMed]
  54. Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2, 1231–1246. [Google Scholar] [CrossRef]
  55. Yalçın, S.; Karakaş, Ö.; Okudan, E.Ş.; Kocaoba, S.; Apak, M.R. Comparative Spectrophotometric and Chromatographic Assessment of Antioxidant Capacity in Different Marine Algae. J. Aquat. Food Prod. Technol. 2023, 32, 81–94. [Google Scholar] [CrossRef]
  56. de Cedrón, M.G.; Vargas, T.; Madrona, A.; Jiménez, A.; Pérez-Pérez, M.-J.; Quintela, J.-C.; Reglero, G.; San-Felix, A.R.; de Molina, A.R. Novel Polyphenols That Inhibit Colon Cancer Cell Growth Affecting Cancer Cell Metabolism. J. Pharmacol. Exp. Ther. 2018, 366, 377–389. [Google Scholar] [CrossRef] [PubMed]
  57. Ruzzolini, J.; Peppicelli, S.; Bianchini, F.; Andreucci, E.; Urciuoli, S.; Romani, A.; Tortora, K.; Caderni, G.; Nediani, C.; Calorini, L. Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract. Cancers 2020, 12, 317. [Google Scholar] [CrossRef] [PubMed]
  58. Mateos, R.; Pérez-Correa, J.R.; Domínguez, H. Bioactive Properties of Marine Phenolics. Mar. Drugs 2020, 18, 501. [Google Scholar] [CrossRef] [PubMed]
  59. Lim, S.N.; Cheung, P.C.K.; Ooi, V.E.C.; Ang, P.O. Evaluation of antioxidative activity of extracts from a brown seaweed, Sargassum siliquastrum. J. Agric. Food Chem. 2002, 50, 3862–3866. [Google Scholar] [CrossRef] [PubMed]
  60. Lee, S.-H.; Li, Y.; Karadeniz, F.; Kim, M.-M.; Kim, S.-K. α-Glucosidase and α-amylase inhibitory activities of phloroglucinal derivatives from edible marine brown alga, Ecklonia cava. J. Sci. Food Agric. 2009, 89, 1552–1558. [Google Scholar] [CrossRef]
  61. Lee, S.-H.; Kang, S.-M.; Ko, S.-C.; Kang, M.-C.; Jeon, Y.-J. Octaphlorethol A, a novel phenolic compound isolated from Ishige foliacea, protects against streptozotocin-induced pancreatic β cell damage by reducing oxidative stress and apoptosis. Food Chem. Toxicol. 2013, 59, 643–649. [Google Scholar] [CrossRef] [PubMed]
  62. Lee, S.-H.; Park, M.-H.; Heo, S.-J.; Kang, S.-M.; Ko, S.-C.; Han, J.-S.; Jeon, Y.-J. Dieckol isolated from Ecklonia cava inhibits α-glucosidase and α-amylase in vitro and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice. Food Chem. Toxicol. 2010, 48, 2633–2637. [Google Scholar] [CrossRef] [PubMed]
  63. Murray, M.; Dordevic, A.L.; Ryan, L.; Bonham, M.P. The Impact of a Single Dose of a Polyphenol-Rich Seaweed Extract on Postprandial Glycaemic Control in Healthy Adults: A Randomised Cross-Over Trial. Nutrients 2018, 10, 270. [Google Scholar] [CrossRef]
  64. Kang, M.-C.; Wijesinghe, W.; Lee, S.-H.; Kang, S.-M.; Ko, S.-C.; Yang, X.; Kang, N.; Jeon, B.-T.; Kim, J.; Lee, D.-H.; et al. Dieckol isolated from brown seaweed Ecklonia cava attenuates type II diabetes in db/db mouse model. Food Chem. Toxicol. 2013, 53, 294–298. [Google Scholar] [CrossRef] [PubMed]
  65. Eo, H.; Jeon, Y.; Lee, M.; Lim, Y. Brown Alga Ecklonia cava polyphenol extract ameliorates hepatic lipogenesis, oxidative stress, and inflammation by activation of AMPK and SIRT1 in high-fat diet-induced obese mice. J. Agric. Food Chem. 2015, 63, 349–359. [Google Scholar] [CrossRef] [PubMed]
  66. Lee, S.; Youn, K.; Kim, D.H.; Ahn, M.-R.; Yoon, E.; Kim, O.-Y.; Jun, M. Anti-Neuroinflammatory Property of Phlorotannins from Ecklonia cava on Aβ25-35-Induced Damage in PC12 Cells. Mar. Drugs 2018, 17, 7. [Google Scholar] [CrossRef] [PubMed]
  67. Pacheco, L.V.; Parada, J.; Pérez-Correa, J.R.; Mariotti-Celis, M.S.; Erpel, F.; Zambrano, A.; Palacios, M. Bioactive Polyphenols from Southern Chile Seaweed as Inhibitors of Enzymes for Starch Digestion. Mar. Drugs 2020, 18, 353. [Google Scholar] [CrossRef] [PubMed]
  68. Heffernan, N.; Brunton, N.P.; FitzGerald, R.J.; Smyth, T.J. Profiling of the molecular weight and structural isomer abundance of macroalgae-derived phlorotannins. Mar. Drugs 2015, 13, 509–528. [Google Scholar] [CrossRef] [PubMed]
  69. Yoon, J.S.; Yadunandam, A.K.; Kim, S.J.; Woo, H.C.; Kim, H.R.; Kim, G.D. Dieckol, isolated from Ecklonia stolonifera, induces apoptosis in human hepatocellular carcinoma Hep3B cells. J. Nat. Med. 2013, 67, 519–527. [Google Scholar] [CrossRef] [PubMed]
  70. Wang, C.H.; Li, X.F.; Jin, L.F.; Zhao, Y.; Zhu, G.J.; Shen, W.Z. Dieckol inhibits non-small-cell lung cancer cell proliferation and migration by regulating the PI3K/AKT signaling pathway. J. Biochem. Mol. Toxicol. 2019, 33, e22346. [Google Scholar] [CrossRef] [PubMed]
  71. Jeong, S.H.; Jeon, Y.J.; Park, S.J. Inhibitory effects of dieckol on hypoxia-induced epithelial-mesenchymal transition of HT29 human colorectal cancer cells. Mol. Med. Rep. 2016, 14, 5148–5154. [Google Scholar] [CrossRef] [PubMed]
  72. Kang, H.S.; Chung, H.Y.; Kim, J.Y.; Son, B.W.; Jung, H.A.; Choi, J.S. Inhibitory phlorotannins from the edible brown algaecklonia stolonifera on total reactive oxygen species (ROS) generation. Arch. Pharm. Res. 2004, 27, 194–198. [Google Scholar] [CrossRef] [PubMed]
  73. Park, S.J.; Jeon, Y.J. Dieckol from Ecklonia cava suppresses the migration and invasion of HT1080 cells by inhibiting the focal adhesion kinase pathway downstream of Rac1-ROS signaling. Mol. Cells 2012, 33, 141–149. [Google Scholar] [CrossRef]
  74. Park, S.J.; Kim, Y.T.; Jeon, Y.J. Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Mol. Cells 2012, 33, 363–369. [Google Scholar] [CrossRef] [PubMed]
  75. Sadeeshkumar, V.; Duraikannu, A.; Ravichandran, S.; Fredrick, W.S.; Sivaperumal, R.; Kodisundaram, P. Protective effects of dieckol on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biomed. Pharmacother. 2016, 84, 1810–1819. [Google Scholar] [CrossRef] [PubMed]
  76. Sadeeshkumar, V.; Duraikannu, A.; Ravichandran, S.; Kodisundaram, P.; Fredrick, W.S.; Gobalakrishnan, R. Modulatory efficacy of dieckol on xenobiotic-metabolizing enzymes, cell proliferation, apoptosis, invasion and angiogenesis during NDEA-induced rat hepatocarcinogenesis. Mol. Cell. Biochem. 2017, 433, 195–204. [Google Scholar] [CrossRef] [PubMed]
  77. Zhang, M.Y.; Guo, J.; Hu, X.M.; Zhao, S.Q.; Li, S.L.; Wang, J. An in vivo anti-tumor effect of eckol from marine brown algae by improving the immune response. Food Funct. 2019, 10, 4361–4371. [Google Scholar] [CrossRef] [PubMed]
  78. Wiechmann, K.; Müller, H.; Fischer, D.; Jauch, J.; Werz, O. The acylphloroglucinols hyperforin and myrtucommulone A cause mitochondrial dysfunctions in leukemic cells by direct interference with mitochondria. Apoptosis 2015, 20, 1508–1517. [Google Scholar] [CrossRef] [PubMed]
  79. Menegazzi, M.; Masiello, P.; Novelli, M. Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics. Antioxidants 2020, 10, 18. [Google Scholar] [CrossRef] [PubMed]
  80. Manna, S.K.; Golla, S.; Golla, J.P.; Tanaka, N.; Cai, Y.; Takahashi, S.; Krausz, K.W.; Matsubara, T.; Korboukh, I.; Gonzalez, F.J.S. John’s Wort Attenuates Colorectal Carcinogenesis in Mice through Suppression of Inflammatory Signaling. Cancer Prev. Res. 2015, 8, 786–795. [Google Scholar] [CrossRef]
  81. Hsu, F.-T.; Chen, W.-T.; Wu, C.-T.; Chung, J.-G. Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits EGFR/ERK/NF-κB-mediated anti-apoptotic potential in glioblastoma. Environ. Toxicol. 2020, 35, 1058–1069. [Google Scholar] [CrossRef]
  82. Chiang, I.-T.; Chen, W.-T.; Tseng, C.-W.; Chen, Y.-C.; Kuo, Y.-C.; Chen, B.-J.; Weng, M.-C.; Lin, H.-J.; Wang, W.-S. Hyperforin Inhibits Cell Growth by Inducing Intrinsic and Extrinsic Apoptotic Pathways in Hepatocellular Carcinoma Cells. Anticancer Res. 2017, 37, 161–167. [Google Scholar] [CrossRef] [PubMed]
  83. Catarino, M.D.; Fernandes, I.; Oliveira, H.; Carrascal, M.; Ferreira, R.; Silva, A.M.S.; Cruz, M.T.; Mateus, N.; Cardoso, S.M. Antitumor Activity of Fucus vesiculosus-Derived Phlorotannins through Activation of Apoptotic Signals in Gastric and Colorectal Tumor Cell Lines. Int. J. Mol. Sci. 2021, 22, 7604. [Google Scholar] [CrossRef] [PubMed]
  84. Dutot, M.; Olivier, E.; Fouyet, S.; Magny, R.; Hammad, K.; Roulland, E.; Rat, P.; Fagon, R. In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzo[a]pyrene-Induced P2X7 Activation and Toxic Effects. Mar. Drugs 2021, 19, 34. [Google Scholar] [CrossRef] [PubMed]
  85. Zhang, S.; Ren, H.; Sun, H.; Cao, S. Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway. Saudi J. Biol. Sci. 2021, 28, 4908–4915. [Google Scholar] [CrossRef] [PubMed]
  86. Olasehinde, T.A.; Olaniran, A.O. Antiproliferative and apoptosis—Inducing effects of aqueous extracts from Ecklonia maxima and Ulva rigida on HepG2 cells. J. Food Biochem. 2022, 46, e14498. [Google Scholar] [CrossRef]
  87. Ahn, J.H.; Yang, Y.I.; Lee, K.T.; Choi, J.H. Dieckol, isolated from the edible brown algae Ecklonia cava, induces apoptosis of ovarian cancer cells and inhibits tumor xenograft growth. J. Cancer Res. Clin. Oncol. 2015, 141, 255–268. [Google Scholar] [CrossRef]
  88. Yang, Y.I.; Ahn, J.H.; Choi, Y.S.; Choi, J.H. Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity. Gynecol. Oncol. 2015, 136, 355–364. [Google Scholar] [CrossRef]
  89. Pradhan, B.; Bhuyan, P.P.; Ki, J.S. Immunomodulatory, Antioxidant, Anticancer, and Pharmacokinetic Activity of Ulvan, a Seaweed-Derived Sulfated Polysaccharide: An Updated Comprehensive Review. Mar. Drugs 2023, 21, 300. [Google Scholar] [CrossRef]
  90. Truzzi, F.; Tibaldi, C.; Zhang, Y.; Dinelli, G.; D’Amen, E. An overview on dietary polyphenols and their biopharmaceutical classification system (Bcs). Int. J. Mol. Sci. 2021, 22, 5514. [Google Scholar] [CrossRef]
  91. Catarino, M.D.; Circuncisão, A.R.; Neves, B.; Marçal, C.; Silva, A.M.S.; Cruz, M.T.; Cardoso, S.M. Impact of Gastrointestinal Digestion on the Anti-Inflammatory Properties of Phlorotannins from Himanthalia elongata. Antioxidants 2022, 11, 1518. [Google Scholar] [CrossRef] [PubMed]
  92. Meng, W.; Mu, T.; Sun, H.; Garcia-Vaquero, M. Phlorotannins: A review of extraction methods, structural characteristics, bioactivities, bioavailability, and future trends. Algal Res. 2021, 60, 102484. [Google Scholar] [CrossRef]
  93. Cassani, L.; Gomez-Zavaglia, A.; Jimenez-Lopez, C.; Lourenço-Lopes, C.; Prieto, M.A.; Simal-Gandara, J. Seaweed-based natural ingredients: Stability of phlorotannins during extraction, storage, passage through the gastrointestinal tract and potential incorporation into functional foods. Food Res. Int. 2020, 137, 109676. [Google Scholar] [CrossRef] [PubMed]
  94. Hosseini, S.F.; Ramezanzade, L.; McClements, D.J. Recent advances in nanoencapsulation of hydrophobic marine bioactives: Bioavailability, safety, and sensory attributes of nano-fortified functional foods. Trends Food Sci. Technol. 2021, 109, 322–339. [Google Scholar] [CrossRef]
  95. Kaushalya, K.G.D.; Gunathilake, K.D.P.P. Encapsulation of phlorotannins from edible brown seaweed in chitosan: Effect of fortification on bioactivity and stability in functional foods. Food Chem. 2022, 377, 132012. [Google Scholar] [CrossRef] [PubMed]
  96. Benavides, S.; Cortés, P.; Parada, J.; Franco, W. Development of alginate microspheres containing thyme essential oil using ionic gelation. Food Chem. 2016, 204, 77–83. [Google Scholar] [CrossRef] [PubMed]
  97. Zhang, T.; Lv, C.; Chen, L.; Bai, G.; Zhao, G.; Xu, C. Encapsulation of anthocyanin molecules within a ferritin nanocage increases their stability and cell uptake efficiency. Food Res. Int. 2014, 62, 183–192. [Google Scholar] [CrossRef]
  98. Petrotos, K.B.; Karkanta, F.K.; Gkoutsidis, P.E.; Giavasis, I.; Papatheodorou, K.N.; Ntontos, A.C. Production of Novel Bioactive Yogurt Enriched with Olive Fruit Polyphenols. World Acad. Sci. Eng. Technol. 2012, 64, 867–872. [Google Scholar] [CrossRef]
  99. Franco, W.; Arazo, M.C.R.; Benavides, S. Recent advances in the encapsulation of marine phenolic compounds. In Marine Phenolic Compounds: Science and Engineering; Elsevier: Amsterdam, The Netherlands, 2023; pp. 239–264. [Google Scholar] [CrossRef]
  100. Cuong, D.X. Antioxidant Nano Phlorotannin Powder from Brown Algae Sargassum serratum: Spray Drying, Antioxidant Activities, Physic-Chemical Characterization. J. Pharm. Res. Int. 2020, 32, 71–85. [Google Scholar] [CrossRef]
  101. Nkurunziza, D.; Sivagnanam, S.P.; Park, J.S.; Cho, Y.J.; Chun, B.S. Effect of wall materials on the spray drying encapsulation of brown seaweed bioactive compounds obtained by subcritical water extraction. Algal Res. 2021, 58, 102381. [Google Scholar] [CrossRef]
  102. Anwar, E.; Erianto, H.; Putri, K.S.S. Preparation of powder from brown seaweed (Sargassum plagyophyllum) by freeze-drying with maltodextrin as a stabilizer. Int. J. Appl. Pharm. 2018, 10, 348–353. [Google Scholar] [CrossRef]
  103. Ozkan, G.; Kostka, T.; Esatbeyoglu, T.; Capanoglu, E. Effects of lipid-based encapsulation on the bioaccessibility and bioavailability of phenolic compounds. Molecules 2020, 25, 5545. [Google Scholar] [CrossRef] [PubMed]
  104. Mozafari, M.R.; Johnson, C.; Hatziantoniou, S.; Demetzos, C. Nanoliposomes and their applications in food nanotechnology. J. Liposome Res. 2008, 18, 309–327. [Google Scholar] [CrossRef]
  105. Baskararaj, S.; Panneerselvam, T.; Govindaraj, S.; Arunachalam, S.; Parasuraman, P.; Pandian, S.R.K.; Sankaranarayanan, M.; Mohan, U.P.; Palanisamy, P.; Ravishankar, V. Formulation and characterization of folate receptor-targeted PEGylated liposome encapsulating bioactive compounds from Kappaphycus alvarezii for cancer therapy. 3 Biotech 2020, 10, 136. [Google Scholar] [CrossRef] [PubMed]
  106. Savaghebi, D.; Barzegar, M.; Mozafari, M.R. Manufacturing of nanoliposomal extract from Sargassum boveanum algae and investigating its release behavior and antioxidant activity. Food Sci. Nutr. 2020, 8, 299–310. [Google Scholar] [CrossRef]
  107. Mmola, M.; Le Roes-Hill, M.; Durrell, K.; Bolton, J.J.; Sibuyi, N.; Meyer, M.E.; Beukes, D.R.; Antunes, E. Enhanced antimicrobial and anticancer activity of silver and gold nanoparticles synthesised using Sargassum incisifolium aqueous extracts. Molecules 2016, 21, 1633. [Google Scholar] [CrossRef] [PubMed]
  108. Trojanowska, A.; Nogalska, A.; Valls, R.G.; Giamberini, M.; Tylkowski, B. Technological solutions for encapsulation. Phys. Sci. Rev. 2017, 2, 20170020. [Google Scholar] [CrossRef]
  109. Pateiro, M.; Gómez, B.; Munekata, P.E.S.; Barba, F.J.; Putnik, P.; Kovačević, D.B.; Lorenzo, J.M. Nanoencapsulation of promising bioactive compounds to improve their absorption, stability, functionality and the appearance of the final food products. Molecules 2021, 26, 1547. [Google Scholar] [CrossRef] [PubMed]
  110. Yoshizawa, H. Trends in Microencapsulation Research. KONA Powder Part. J. 2004, 22, 23–31. [Google Scholar] [CrossRef]
  111. Shibata, T.; Ishimaru, K.; Kawaguchi, S.; Yoshikawa, H.; Hama, Y. Antioxidant activities of phlorotannins isolated from Japanese Laminariaceae. J. Appl. Phycol. 2008, 20, 705–711. [Google Scholar] [CrossRef]
  112. Vissers, A.M.; Blok, A.E.; Westphal, A.H.; Hendriks, W.H.; Gruppen, H.; Vincken, J.P. Resolubilization of Protein from Water-Insoluble Phlorotannin-Protein Complexes upon Acidification. J. Agric. Food Chem. 2017, 65, 9595–9602. [Google Scholar] [CrossRef] [PubMed]
  113. Bai, Y.; Sun, Y.; Gu, Y.; Zheng, J.; Yu, C.; Qi, H. Preparation, characterization and antioxidant activities of kelp phlorotannin nanoparticles. Molecules 2020, 25, 4550. [Google Scholar] [CrossRef] [PubMed]
  114. Jiang, D.; Shen, P.; Pu, Y.; Jin, M.; Yu, C.; Qi, H. Enhancement of gel properties of Scomberomorus niphonius myofibrillar protein using phlorotannin extracts under UVA irradiation. J. Food Sci. 2020, 85, 2050–2059. [Google Scholar] [CrossRef] [PubMed]
  115. Liu, N.; Fu, X.; Duan, D.; Xu, J.; Gao, X.; Zhao, L. Evaluation of bioactivity of phenolic compounds from the brown seaweed of Sargassum fusiforme and development of their stable emulsion. J. Appl. Phycol. 2018, 30, 1955–1970. [Google Scholar] [CrossRef]
  116. Venkatesan, J.; Kim, S.K.; Shim, M.S. Antimicrobial, antioxidant, and anticancer activities of biosynthesized silver nanoparticles using marine algae Ecklonia cava. Nanomaterials 2016, 6, 235. [Google Scholar] [CrossRef] [PubMed]
  117. Surendhiran, D.; Cui, H.; Lin, L. Encapsulation of Phlorotannin in Alginate/PEO blended nanofibers to preserve chicken meat from Salmonella contaminations. Food Packag. Shelf Life 2019, 21, 100346. [Google Scholar] [CrossRef]
  118. Cui, H.; Yang, X.; Abdel-Samie, M.A.; Lin, L. Cold plasma treated phlorotannin/Momordica charantia polysaccharide nanofiber for active food packaging. Carbohydr. Polym. 2020, 239, 116214. [Google Scholar] [CrossRef] [PubMed]
  119. O’Sullivan, A.M.; O’Callaghan, Y.C.; O’Grady, M.N.; Waldron, D.S.; Smyth, T.J.; O’Brien, N.M.; Kerry, J.P. An examination of the potential of seaweed extracts as functional ingredients in milk. Int. J. Dairy Technol. 2014, 67, 182–193. [Google Scholar] [CrossRef]
  120. Rønne, M.E.; Madsen, M.; Tandrup, T.; Wilkens, C.; Svensson, B. Gut bacterial alginate degrading enzymes. Essays Biochem. 2023, 67, 387–398. [Google Scholar] [CrossRef] [PubMed]
  121. Kaczmarek, M.B.; Struszczyk-Swita, K.; Li, X.; Szczęsna-Antczak, M.; Daroch, M. Enzymatic modifications of chitin, chitosan, and chitooligosaccharides. Front. Bioeng. Biotechnol. 2019, 7, 243. [Google Scholar] [CrossRef] [PubMed]
  122. Kulkarni, S.A.; Feng, S.S. Effects of particle size and surface modification on cellular uptake and biodistribution of polymeric nanoparticles for drug delivery. Pharm. Res. 2013, 30, 2512–2522. [Google Scholar] [CrossRef] [PubMed]
  123. Zhao, Y.; Wang, Y.; Ran, F.; Cui, Y.; Liu, C.; Zhao, Q.; Gao, Y.; Wang, D.; Wang, S. A comparison between sphere and rod nanoparticles regarding their in vivo biological behavior and pharmacokinetics. Sci. Rep. 2017, 7, 4131. [Google Scholar] [CrossRef] [PubMed]
  124. Rewatkar, P.; Kumeria, T.; Popat, A. Size, shape and surface charge considerations of orally delivered nanomedicines. In Nanotechnology for Oral Drug Delivery: From Concept to Applications; Elsevier: Amsterdam, The Netherlands, 2020; pp. 143–176. [Google Scholar] [CrossRef]
  125. De Jong, W.H.; Borm, P.J. Drug delivery and nanoparticles: Applications and hazards. Int. J. Nanomed. 2008, 3, 133–149. [Google Scholar] [CrossRef] [PubMed]
  126. Ensign, L.M.; Cone, R.; Hanes, J. Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers. Adv. Drug Deliv. Rev. 2012, 64, 557–570. [Google Scholar] [CrossRef] [PubMed]
  127. Lamson, N.G.; Berger, A.; Fein, K.C.; Whitehead, K.A. Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability. Nat. Biomed. Eng. 2020, 4, 84–96. [Google Scholar] [CrossRef] [PubMed]
Antioxidants 12 01734 g001
Figure 1. Factors affecting phlorotannins effectiveness as a biopharmaceutical product.
Figure 1. Factors affecting phlorotannins effectiveness as a biopharmaceutical product.
Antioxidants 12 01734 g001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Simón, L.; Arazo-Rusindo, M.; Quest, A.F.G.; Mariotti-Celis, M.S. Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer. Antioxidants 2023, 12, 1734. https://doi.org/10.3390/antiox12091734

AMA Style

Simón L, Arazo-Rusindo M, Quest AFG, Mariotti-Celis MS. Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer. Antioxidants. 2023; 12(9):1734. https://doi.org/10.3390/antiox12091734

Chicago/Turabian Style

Simón, Layla, Migdalia Arazo-Rusindo, Andrew F. G. Quest, and María Salomé Mariotti-Celis. 2023. "Phlorotannins: Novel Orally Administrated Bioactive Compounds That Induce Mitochondrial Dysfunction and Oxidative Stress in Cancer" Antioxidants 12, no. 9: 1734. https://doi.org/10.3390/antiox12091734

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop