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Natural Bioactives and Phytochemicals in Cancer Prevention

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 July 2018) | Viewed by 149280

Special Issue Editor

Special Issue Information

Dear Colleagues,

Natural bioactives, or phytochemicals, generally refer to compounds exclusive to essential nutrients that have specific biological activities in humans. It is known that over 10,000 different phytochemicals possess potential preventive or supplementary effects on various diseases. Studies have shown that natural phytochemicals derived from certain plants have the capability to prevent carcinogenesis. Therefore, new active compounds responsible for the anti-cancer characteristics of dietary plants, and original active compounds exert novel function on anti-carcinogenesis, are important issues in cancer investigation. We invite the researchers to contribute original and review articles regarding the relationship between phytochemicals and cancers, including the discovery of novel anti-cancer phytochemicals and the novel signalling pathways, and signalling molecules of phytochemicals on cancer treatment.

Prof. Dr. Shun-Fa Yang
Guest Editor

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Keywords

  • natural bioactives
  • phytochemicals
  • cancer
  • metastasis
  • apoptosis

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Published Papers (21 papers)

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19 pages, 1575 KiB  
Article
Effect of Roasting Levels and Drying Process of Coffea canephora on the Quality of Bioactive Compounds and Cytotoxicity
by Deborah Bauer, Joel Abreu, Nathállia Jordão, Jeane Santos da Rosa, Otniel Freitas-Silva and Anderson Teodoro
Int. J. Mol. Sci. 2018, 19(11), 3407; https://doi.org/10.3390/ijms19113407 - 31 Oct 2018
Cited by 28 | Viewed by 5851
Abstract
Coffee is a popular drink consumed all over the world. Besides its long-recognized stimulant effect, it has important nutritional and health effects. However, the type of bean processing modifies the composition of brewed coffee and possibly its bioactivity. In this study, extracts obtained [...] Read more.
Coffee is a popular drink consumed all over the world. Besides its long-recognized stimulant effect, it has important nutritional and health effects. However, the type of bean processing modifies the composition of brewed coffee and possibly its bioactivity. In this study, extracts obtained from green and roasted beans of Coffea canephora (Coffea canephora var. robusta) were submitted to spray- or freeze-drying and were tested for antiproliferative activity, using MTT assay, and their influence on the cell cycle and apoptosis by flow cytometry analysis. Moreover, colors and nutrient contents were measured to identify the changes due to the roasting process. The results obtained showed that extracts from green and light roasted beans exhibited strong bioactive capacity. Coffee extracts promoted a decrease in cell viability, modulated cell cycle and induced apoptosis in human prostate carcinoma cell line (DU-145). The level of roasting reduced this property, but the type of drying did not in all cases. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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17 pages, 3630 KiB  
Article
Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism
by Young-Seon Kim, Yoon-Mi Lee, Taek-In Oh, Dong Hoon Shin, Geon-Hee Kim, Sang-Yeon Kan, Hyeji Kang, Ji Hyung Kim, Byeong Mo Kim, Woo Jong Yim and Ji-Hong Lim
Int. J. Mol. Sci. 2018, 19(10), 3127; https://doi.org/10.3390/ijms19103127 - 12 Oct 2018
Cited by 72 | Viewed by 5674
Abstract
Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the [...] Read more.
Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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15 pages, 2740 KiB  
Article
Zingerone Suppresses Tumor Development through Decreasing Cyclin D1 Expression and Inducing Mitotic Arrest
by Jae-Sun Choi, Jaewook Ryu, Woom-Yee Bae, Aron Park, Seungyoon Nam, Ja-Eun Kim and Joo-Won Jeong
Int. J. Mol. Sci. 2018, 19(9), 2832; https://doi.org/10.3390/ijms19092832 - 19 Sep 2018
Cited by 30 | Viewed by 4780
Abstract
Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, [...] Read more.
Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, is a nontoxic and inexpensive compound with varied pharmacological activities. In this study, the therapeutic effect of zingerone as an anti-mitotic agent in human neuroblastoma cells was investigated. Following treatment of BE(2)-M17 cells with zingerone, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and colony-formation assay to evaluate cellular proliferation, in addition to immunofluorescence cytochemistry and flow cytometry to examine the mitotic cells. The association of gene expression with tumor stage and survival was analyzed. Furthermore, to examine the anti-cancer effect of zingerone, we applied a BALB/c mouse-tumor model using a BALB/c-derived adenocarcinoma cell line. In human neuroblastoma cells, zingerone inhibited cellular viability and survival. Moreover, the number of mitotic cells, particularly those in prometaphase, increased in zingerone-treated neuroblastoma cells. Regarding specific molecular mechanisms, zingerone decreased cyclin D1 expression and induced the cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The decrease in cyclin D1 and increase in histone H3 phosphorylated (p)-Ser10 were confirmed by immunohistochemistry in tumor tissues administered with zingerone. These results suggest that zingerone induces mitotic arrest followed by inhibition of growth of neuroblastoma cells. Collectively, zingerone may be a potential therapeutic drug for human cancers, including neuroblastoma. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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22 pages, 6134 KiB  
Article
Th1-Biased Immunomodulation and In Vivo Antitumor Effect of a Novel Piperine Analogue
by Jephesson Santos, Monalisa Brito, Rafael Ferreira, Ana Paula Moura, Tatyanna Sousa, Tatianne Batista, Vivianne Mangueira, Fagner Leite, Ryldene Cruz, Giciane Vieira, Bruno Lira, Petrônio Athayde-Filho, Helivaldo Souza, Normando Costa, Robson Veras, José Maria Barbosa-Filho, Hemerson Magalhães and Marianna Sobral
Int. J. Mol. Sci. 2018, 19(9), 2594; https://doi.org/10.3390/ijms19092594 - 01 Sep 2018
Cited by 19 | Viewed by 4096
Abstract
Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity [...] Read more.
Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 µg/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1β, TNF-α, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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23 pages, 3670 KiB  
Article
Evaluation of In Vitro Antioxidant and Anticancer Properties of the Aqueous Extract from the Stem Bark of Stryphnodendron adstringens
by Débora Da Silva Baldivia, Daniel Ferreira Leite, David Tsuyoshi Hiramatsu de Castro, Jaqueline Ferreira Campos, Uilson Pereira dos Santos, Edgar Julian Paredes-Gamero, Carlos Alexandre Carollo, Denise Brentan Silva, Kely De Picoli Souza and Edson Lucas Dos Santos
Int. J. Mol. Sci. 2018, 19(8), 2432; https://doi.org/10.3390/ijms19082432 - 17 Aug 2018
Cited by 32 | Viewed by 4642
Abstract
Stryphnodendron adstringens (Mart.) Coville (Fabaceae) is a tree species native to the Brazilian Cerrado commonly known as barbatimão. In traditional medicine, decoctions or infusions of the stem bark of this plant are used in the treatment of several diseases. The objective of this [...] Read more.
Stryphnodendron adstringens (Mart.) Coville (Fabaceae) is a tree species native to the Brazilian Cerrado commonly known as barbatimão. In traditional medicine, decoctions or infusions of the stem bark of this plant are used in the treatment of several diseases. The objective of this study was to analyze the chemical composition of Stryphnodendron adstringens aqueous extracts (SAAE) prepared from the stem bark to assess their antioxidant activity and anticancer effects as well as characterize cell death mechanisms against murine B16F10Nex-2 melanoma cells. From the SAAE, gallic acid, gallocatechin, epigallocatechin, dimeric and trimeric proanthocyanidins mainly composed of prodelphinidin units and the isomeric chromones C-hexosyl- and O-pentosyl-5,7-dihydroxychromone were identified. The SAAE showed antioxidant activity through direct free-radical scavenging as well as through oxidative hemolysis and lipid peroxidation inhibition in human erythrocytes. Furthermore, SAAE promoted apoptosis-induced cell death in melanoma cells by increasing intracellular reactive oxygen species (ROS) levels, inducing mitochondrial membrane potential dysfunction and activating caspase-3. Together, these data show the antioxidant and anticancer effects of Stryphnodendron adstringens. These results open new perspectives for studies against other tumor cell lines and in vivo models as well as for the identification and isolation of the chemical constituents responsible for these effects. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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23 pages, 5450 KiB  
Article
Ethyl Acetate Extract of Scindapsus cf. hederaceus Exerts the Inhibitory Bioactivity on Human Non-Small Cell Lung Cancer Cells through Modulating ER Stress
by Chon-Kit Chou, Wangta Liu, Yu-Jie Hong, Hans-Uwe Dahms, Chen-Hao Chiu, Wen-Tsan Chang, Ching-Ming Chien, Chia-Hung Yen, Yuan-Bin Cheng and Chien-Chih Chiu
Int. J. Mol. Sci. 2018, 19(7), 1832; https://doi.org/10.3390/ijms19071832 - 21 Jun 2018
Cited by 11 | Viewed by 4774
Abstract
Unfolded protein response (UPR) is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER) homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of [...] Read more.
Unfolded protein response (UPR) is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER) homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of various malignant phenotypes including cell proliferation, migration, and invasion, as well as angiogenesis. This suggests UPR as a promising target in cancer therapy. The pharmacological effects of the plant Scindapsus cf. hederaceus on human cancer cell lines is not understood. In this study, we identified an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE), which markedly altered the protein expression of UPR-related genes in human non-small cell lung cancer (NSCLC) cells. Treatment with the SH-EAE led to the dose-dependent suppression of colony forming ability of both H1299 and H460 cells, but not markedly in normal bronchial epithelial BEAS-2B cells. SH-EAE treatment also attenuated the migration and invasion ability of H1299 and H460 cells. Moreover, SH-EAE strikingly suppressed the protein expression of two ER stress sensors, including inositol requiring enzyme-1α (IRE-1α) and protein kinase R-like ER kinase (PERK), and antagonized the induction of C/EBP homologous protein (CHOP) expression by thapsigargin, an ER stress inducer. SH-EAE induced the formation of massive vacuoles which are probably derived from ER. Importantly, SH-EAE impaired the formation of intersegmental vessels (ISV) in zebrafish larvae, an index of angiogenesis, but had no apparent effect on the rate of larval development. Together, our findings demonstrate, for the first time, that the ability of SH-EAE specifically targets the two sensors of UPR, with significant anti-proliferation and anti-migration activities as a crude extract in human NSCLC cells. Our finding also indicates potential applications of SH-EAE in preventing UPR activation in response to Tg-induced ER stress. We suggest that SH-EAE attenuates UPR adaptive pathways for rendering the NSCLC cells intolerant to ER stress. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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14 pages, 2345 KiB  
Article
Synergistic Antitumor Effect of Oligogalacturonides and Cisplatin on Human Lung Cancer A549 Cells
by Cian-Song Huang, Ai-Chun Huang, Ping-Hsiu Huang, Diana Lo, Yuh-Tai Wang and Ming-Chang Wu
Int. J. Mol. Sci. 2018, 19(6), 1769; https://doi.org/10.3390/ijms19061769 - 14 Jun 2018
Cited by 5 | Viewed by 5633
Abstract
Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had [...] Read more.
Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had a synergistic effect on the growth inhibition of A549 cells, changed the cell cycle distribution, and enhanced apoptotic response, especially in sequential combination treatment group of DDP 12 h + OGA 12 h. Western blot analyses showed that the combination treatment of OGA and DDP upregulated Bax, p53, and Caspase-3 and downregulated Bcl-2 proteins. More importantly, DDP-induced toxicity was attenuated by OGA and DDP combination treatment in normal HEK293 cells. Our data suggests that the combined use of OGA from natural sources and DDP could be an important new adjuvant therapy for lung cancer as well as offer important insights for reducing kidney toxicity of DDP and delaying the development of DDP resistance. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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20 pages, 8521 KiB  
Article
Response of Myeloid Leukemia Cells to Luteolin is Modulated by Differentially Expressed Pituitary Tumor-Transforming Gene 1 (PTTG1) Oncoprotein
by Pei-Yi Chen, Hsin-Jung Tien, Shih-Fen Chen, Chi-Ting Horng, Huei-Lin Tang, Hui-Ling Jung, Ming-Jiuan Wu and Jui-Hung Yen
Int. J. Mol. Sci. 2018, 19(4), 1173; https://doi.org/10.3390/ijms19041173 - 12 Apr 2018
Cited by 13 | Viewed by 5785
Abstract
Luteolin, a flavonoid nutraceutical abundant in vegetables and fruits, exhibits a wide range of bioactive properties, including antioxidant, anti-inflammatory and anti-cancer activities. Pituitary tumor-transforming gene 1 (PTTG1), an oncoprotein that regulates cell proliferation, is highly expressed in several types of cancer cells including [...] Read more.
Luteolin, a flavonoid nutraceutical abundant in vegetables and fruits, exhibits a wide range of bioactive properties, including antioxidant, anti-inflammatory and anti-cancer activities. Pituitary tumor-transforming gene 1 (PTTG1), an oncoprotein that regulates cell proliferation, is highly expressed in several types of cancer cells including leukemia. In this study, we aim to investigate the anti-cancer effects of luteolin on cells with differential PTTG1 expression and their underlying mechanisms in human myeloid leukemia cells. Methyl thiazolyl tetrazolium (MTT) assay data showed that luteolin (25–100 μM) significantly reduced cell viability in THP-1, HL-60 and K562 cells but did not affect normal peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis and Western blot data demonstrated that luteolin induced a stronger apoptosis on undifferentiated myeloid leukemia cells with higher PTTG1 protein levels than on 12-myristate 13-acetate (PMA)- or all-trans-retinoic acid (ATRA)-differentiated cells with lower PTTG1 expression. Furthermore, PTTG1 knockdown by shRNA in leukemia cells suppressed cell proliferation, arrested cell-cycle progression and impaired the effectiveness of luteolin on cell-cycle regulation. Moreover, PTTG1-knockdown cells with luteolin exposure presented a reduction of the apoptotic proteins and maintained higher levels of the anti-apoptotic proteins such as Mcl-1, Bcl-2 and p21, which exhibited greater resistance to apoptosis. Finally, microarray analysis showed that 20 genes associated with cell proliferation, such as CXCL10, VEGFA, TNF, TP63 and FGFR1, were dramatically down-regulated in PTTG1-knockdown cells. Our current findings clearly demonstrate that luteolin-triggered leukemic cell apoptosis is modulated by the differential expression of the PTTG1. PTTG1 oncoprotein overexpression may modulate cell proliferation-related regulators and enhance the response of myeloid leukemia cells to luteolin. Luteolin is beneficial for the treatment of cancer cells with highly expressed PTTG1 oncoprotein. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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16 pages, 2397 KiB  
Article
DK1 Induces Apoptosis via Mitochondria-Dependent Signaling Pathway in Human Colon Carcinoma Cell Lines In Vitro
by Yazmin Hussin, Muhammad Nazirul Mubin Aziz, Nurul Fattin Che Rahim, Swee Keong Yeap, Nurul Elyani Mohamad, Mas Jaffri Masarudin, Noraini Nordin, Nik Mohd Afizan-Nik Abd Rahman, Chean Yeah Yong, Muhammad Nadeem Akhtar, Siti Noor Hajar Zamrus and Noorjahan Banu Alitheen
Int. J. Mol. Sci. 2018, 19(4), 1151; https://doi.org/10.3390/ijms19041151 - 11 Apr 2018
Cited by 14 | Viewed by 4739
Abstract
Extensive research has been done in the search for innovative treatments against colon adenocarcinomas; however, the incidence rate of patients remains a major cause of cancer-related deaths in Malaysia. Natural bioactive compounds such as curcumin have been substantially studied as an alternative to [...] Read more.
Extensive research has been done in the search for innovative treatments against colon adenocarcinomas; however, the incidence rate of patients remains a major cause of cancer-related deaths in Malaysia. Natural bioactive compounds such as curcumin have been substantially studied as an alternative to anticancer drug therapies and have been surmised as a potent agent but, nevertheless, remain deficient due to its poor cellular uptake. Therefore, efforts now have shifted toward mimicking curcumin to synthesize novel compounds sharing similar effects. A synthetic analog, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-ene-1-one (DK1), was recently synthesized and reported to confer improved bioavailability and selectivity toward human breast cancer cells. This study, therefore, aims to assess the anticancer mechanism of DK1 in relation to the induction of in vitro cell death in selected human colon cancer cell lines. Using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay, the cytotoxicity of DK1 towards HT29 and SW620 cell lines were investigated. Acridine orange/propidium iodide (AO/PI) dual-staining assay and flow cytometry analyses (cell cycle analysis, Annexin/V-FITC and JC-1 assays) were incorporated to determine the mode of cell death. To further determine the mechanism of cell death, quantitative real-time polymerase chain reaction (qRT-PCR) and proteome profiling were conducted. Results from this study suggest that DK1 induced changes in cell morphology, leading to a decrease in cell viability and subsequent induction of apoptosis. DK1 treatment inhibited cell viability and proliferation 48 h post treatment with IC50 values of 7.5 ± 1.6 µM for HT29 cells and 14.5 ± 4.3 µM for SW620 cells, causing cell cycle arrest with increased accumulation of cell populations at the sub-G0/G1phaseof 74% and 23%, respectively. Flow cytometry analyses showed that DK1 treatment in cancer cells induced apoptosis, as indicated by DNA fragmentation and depolarization of the mitochondrial membrane. qRT-PCR results show significant upregulation in the expression of caspase-9 in both HT29 and SW620 cell lines, further supporting that cell death induction by DK1 is via an intrinsic pathway. These outcomes, therefore, demonstrate DK1 as a potential anticancer agent for colon adenocarcinoma due to its anti-apoptotic attributes. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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14 pages, 13497 KiB  
Article
St. John’s Wort Regulates Proliferation and Apoptosis in MCF-7 Human Breast Cancer Cells by Inhibiting AMPK/mTOR and Activating the Mitochondrial Pathway
by Mi-Kyoung You, Hwa-Jin Kim, Ji Hyun Kook and Hyeon-A Kim
Int. J. Mol. Sci. 2018, 19(4), 966; https://doi.org/10.3390/ijms19040966 - 23 Mar 2018
Cited by 31 | Viewed by 5735
Abstract
St. John’s Wort (SJW) has been used as an estrogen agonist in the systems affected by menopause. Also, hypericin, a bioactive compound of SJW, has been used as a photosensitizer in photodynamic therapy. In the present study, we investigate the anti-proliferative and pro-apoptotic [...] Read more.
St. John’s Wort (SJW) has been used as an estrogen agonist in the systems affected by menopause. Also, hypericin, a bioactive compound of SJW, has been used as a photosensitizer in photodynamic therapy. In the present study, we investigate the anti-proliferative and pro-apoptotic effects of SJW to demonstrate the chemo-preventive effect in human breast cancer cells. MCF-7 cells were cultured with DMSO or various concentrations of SJW ethanol extract (SJWE). Cell viability, proliferation, apoptosis, the expression of proteins involved in cell growth and apoptosis, and caspase-3/7 activity were examined. SJWE dose-dependently suppressed cell growth and induced apoptosis of MCF-7 cells. Mechanistically, SJWE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and decreased the expression of p-mammalian target of rapamycin (p-mTOR) and p-eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). Also, SJWE inhibited the phosphorylation of protein kinase B (Akt) and showed increases in the expression of pro-apoptotic proteins Bax and Bad with decreases in the expression of anti-apoptotic proteins including B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), and p-Bcl-2-associated death promoter (p-Bad). SJWE at 50 μg/mL showed markedly enhanced caspase-7 activation. Taken together, our results provide evidence that SJWE shows anti-proliferative and pro-apoptotic effects via inhibition of AMPK/mTOR and activation of a mitochondrial pathway. Therefore, SJWE can be used as a chemo-preventive agent without photo-activation. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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15 pages, 2705 KiB  
Article
Suppression of Cell Growth, Migration and Drug Resistance by Ethanolic Extract of Antrodia cinnamomea in Human Lung Cancer A549 Cells and C57BL/6J Allograft Tumor Model
by Chi-Han Wu, Fon-Chang Liu, Chun-Hsu Pan, Ming-Tsung Lai, Shou-Jen Lan, Chieh-Hsi Wu and Ming-Jyh Sheu
Int. J. Mol. Sci. 2018, 19(3), 791; https://doi.org/10.3390/ijms19030791 - 09 Mar 2018
Cited by 10 | Viewed by 4530
Abstract
The purpose of this study was to investigate the inhibitory activities of ethanolic extracts from Antrodia cinnamomea (EEAC) on lung cancer. Cell proliferation and cell cycle distribution were analyzed using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and flow cytometry, respectively. Wound-healing assay, Western blotting, and [...] Read more.
The purpose of this study was to investigate the inhibitory activities of ethanolic extracts from Antrodia cinnamomea (EEAC) on lung cancer. Cell proliferation and cell cycle distribution were analyzed using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and flow cytometry, respectively. Wound-healing assay, Western blotting, and a murine tumor model were separately used to examine cell migration, protein expression, and tumor repression. Our results showed that EEAC induced cell cycle arrest at the G0/G1 phase resulting decreased cell viability in A549 cells. Moreover, EEAC up-regulated the growth-suppressing proteins, adenosine 5′-monophosphate-activated protein kinase (AMPK), p21 and p27, but down-regulated the growth-promoting proteins, protein kinase B (Akt), mammalian tarfet of rapamycin (mTOR), extracellular signal-regulating kinase 1/2 (ERK1/2), retinoblastoma protein (Rb), cyclin E, and cyclin D1. EEAC also inhibited A549 cell migration and reduced expression of gelatinases. In addition, our data showed that tumor growth was suppressed after treatment with EEAC in a murine allograft tumor model. Some bioactive compounds from EEAC, such as cordycepin and zhankuic acid A, were demonstrated to reduce the protein expressions of matrix metalloproteinase (MMP)-9 and cyclin D1 in A549 cells. Furthermore, EEAC enhanced chemosensitivity of A549 to paclitaxel by reducing the protein levels of caveolin-1. Our data suggests that EEAC has the potential to be an adjuvant medicine for the treatment of lung cancer. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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16 pages, 2341 KiB  
Article
Elucidating the Role of CD84 and AHR in Modulation of LPS-Induced Cytokines Production by Cruciferous Vegetable-Derived Compounds Indole-3-Carbinol and 3,3′-Diindolylmethane
by Thomas T. Y. Wang, Quynhchi Pham and Young S. Kim
Int. J. Mol. Sci. 2018, 19(2), 339; https://doi.org/10.3390/ijms19020339 - 24 Jan 2018
Cited by 16 | Viewed by 5265
Abstract
Modulation of the immune system by cancer protective food bioactives has preventive and therapeutic importance in prostate cancer, but the mechanisms remain largely unclear. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM), affect the [...] Read more.
Modulation of the immune system by cancer protective food bioactives has preventive and therapeutic importance in prostate cancer, but the mechanisms remain largely unclear. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM), affect the tumor microenvironment by regulation of inflammatory responses in monocytes and macrophages. We also ask whether I3C and DIM act through the aryl hydrocarbon (AHR)-dependent pathway or the signaling lymphocyte activation molecule (SLAM) family protein CD84-mediated pathway. The effect of I3C and DIM was examined using the human THP-1 monocytic cell in its un-differentiated (monocyte) and differentiated (macrophage) state. We observed that I3C and DIM inhibited lipopolysaccharide (LPS) induction of IL-1β mRNA and protein in the monocyte form but not the macrophage form of THP-1. Interestingly, CD84 mRNA but not protein was inhibited by I3C and DIM. AHR siRNA knockdown experiments confirmed that the inhibitory effects of I3C and DIM on IL-1β as well as CD84 mRNA are regulated through AHR-mediated pathways. Additionally, the AHR ligand appeared to differentially regulate other LPS-induced cytokines expression. Hence, cross-talk between AHR and inflammation-mediated pathways, but not CD84-mediated pathways, in monocytes but not macrophages may contribute to the modulation of tumor environments by I3C and DIM in prostate cancer. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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14 pages, 3063 KiB  
Article
A Comparative Study on Phytochemical Profiles and Biological Activities of Sclerocarya birrea (A.Rich.) Hochst Leaf and Bark Extracts
by Daniela Russo, Rocchina Miglionico, Monica Carmosino, Faustino Bisaccia, Paula B. Andrade, Patrícia Valentão, Luigi Milella and Maria Francesca Armentano
Int. J. Mol. Sci. 2018, 19(1), 186; https://doi.org/10.3390/ijms19010186 - 08 Jan 2018
Cited by 26 | Viewed by 4868
Abstract
Sclerocarya birrea (A.Rich.) Hochst (Anacardiaceae) is a savannah tree that has long been used in sub-Saharan Africa as a medicinal remedy for numerous ailments. The purpose of this study was to increase the scientific knowledge about this plant by evaluating the total content [...] Read more.
Sclerocarya birrea (A.Rich.) Hochst (Anacardiaceae) is a savannah tree that has long been used in sub-Saharan Africa as a medicinal remedy for numerous ailments. The purpose of this study was to increase the scientific knowledge about this plant by evaluating the total content of polyphenols, flavonoids, and tannins in the methanol extracts of the leaves and bark (MLE and MBE, respectively), as well as the in vitro antioxidant activity and biological activities of these extracts. Reported results show that MLE is rich in flavonoids (132.7 ± 10.4 mg of quercetin equivalents/g), whereas MBE has the highest content of tannins (949.5 ± 29.7 mg of tannic acid equivalents/g). The antioxidant activity was measured using four different in vitro tests: β-carotene bleaching (BCB), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), O2−•, and nitric oxide (NO) assays. In all cases, MBE was the most active compared to MLE and the standards used (Trolox and ascorbic acid). Furthermore, MBE and MLE were tested to evaluate their activity in HepG2 and fibroblast cell lines. A higher cytotoxic activity of MBE was evidenced and confirmed by more pronounced alterations in cell morphology. MBE induced cell death, triggering the intrinsic apoptotic pathway by reactive oxygen species (ROS) generation, which led to a loss of mitochondrial membrane potential with subsequent cytochrome c release from the mitochondria into the cytosol. Moreover, MBE showed lower cytotoxicity in normal human dermal fibroblasts, suggesting its potential as a selective anticancer agent. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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8113 KiB  
Article
Praeruptorin A Inhibits Human Cervical Cancer Cell Growth and Invasion by Suppressing MMP-2 Expression and ERK1/2 Signaling
by Min-Hua Wu, Chia-Liang Lin, Hui-Ling Chiou, Shun-Fa Yang, Ching-Yi Lin, Chung-Jung Liu and Yi-Hsien Hsieh
Int. J. Mol. Sci. 2018, 19(1), 10; https://doi.org/10.3390/ijms19010010 - 21 Dec 2017
Cited by 42 | Viewed by 4957
Abstract
Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell [...] Read more.
Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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Article
Fascaplysin Exerts Anti-Cancer Effects through the Downregulation of Survivin and HIF-1α and Inhibition of VEGFR2 and TRKA
by Taek-In Oh, Yoon-Mi Lee, Taek-Jin Nam, Young-San Ko, Shinmee Mah, Jinhee Kim, Younghoon Kim, Rallabandi Harikrishna Reddy, Young Jun Kim, Sungwoo Hong and Ji-Hong Lim
Int. J. Mol. Sci. 2017, 18(10), 2074; https://doi.org/10.3390/ijms18102074 - 29 Sep 2017
Cited by 26 | Viewed by 5306
Abstract
Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including [...] Read more.
Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB), indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2) and tropomyosin-related kinase A (TRKA) via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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Review

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24 pages, 5545 KiB  
Review
Phytochemicals in Skin Cancer Prevention and Treatment: An Updated Review
by Chau Yee Ng, Hsi Yen, Hui-Yi Hsiao and Shih-Chi Su
Int. J. Mol. Sci. 2018, 19(4), 941; https://doi.org/10.3390/ijms19040941 - 22 Mar 2018
Cited by 64 | Viewed by 10019
Abstract
Skin is the largest human organ, our protection against various environmental assaults and noxious agents. Accumulation of these stress events may lead to the formation of skin cancers, including both melanoma and non-melanoma skin cancers. Although modern targeted therapies have ameliorated the management [...] Read more.
Skin is the largest human organ, our protection against various environmental assaults and noxious agents. Accumulation of these stress events may lead to the formation of skin cancers, including both melanoma and non-melanoma skin cancers. Although modern targeted therapies have ameliorated the management of cutaneous malignancies, a safer, more affordable, and more effective strategy for chemoprevention and treatment is clearly needed for the improvement of skin cancer care. Phytochemicals are biologically active compounds derived from plants and herbal products. These agents appear to be beneficial in the battle against cancer as they exert anti-carcinogenic effects and are widely available, highly tolerated, and cost-effective. Evidence has indicated that the anti-carcinogenic properties of phytochemicals are due to their anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In this review, we discuss the preventive potential, therapeutic effects, bioavailability, and structure–activity relationship of these selected phytochemicals for the management of skin cancers. The knowledge compiled here will provide clues for future investigations on novel oncostatic phytochemicals and additional anti-skin cancer mechanisms. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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40 pages, 12893 KiB  
Review
Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides
by Hee Kyoung Kang, Moon-Chang Choi, Chang Ho Seo and Yoonkyung Park
Int. J. Mol. Sci. 2018, 19(3), 919; https://doi.org/10.3390/ijms19030919 - 20 Mar 2018
Cited by 60 | Viewed by 7377
Abstract
Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells [...] Read more.
Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells through different mechanisms, such as apoptosis, disruption of the tubulin-microtubule balance, and inhibition of angiogenesis. Traditional chemotherapeutic agents have side effects and depress immune responses. Thus, the research and development of novel anticancer peptides with low toxicity to normal human cells and mechanisms of action capable of avoiding multi-drug resistance may provide a new method for anticancer treatment. This review provides useful information on the potential of marine anticancer peptides for human therapy. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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13 pages, 2633 KiB  
Review
Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review
by Yinzhi Lin, Tamami Ukaji, Naoki Koide and Kazuo Umezawa
Int. J. Mol. Sci. 2018, 19(3), 729; https://doi.org/10.3390/ijms19030729 - 03 Mar 2018
Cited by 27 | Viewed by 6962
Abstract
We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of [...] Read more.
We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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13 pages, 849 KiB  
Review
Potential Health Benefits of Olive Oil and Plant Polyphenols
by Monika Gorzynik-Debicka, Paulina Przychodzen, Francesco Cappello, Alicja Kuban-Jankowska, Antonella Marino Gammazza, Narcyz Knap, Michal Wozniak and Magdalena Gorska-Ponikowska
Int. J. Mol. Sci. 2018, 19(3), 686; https://doi.org/10.3390/ijms19030686 - 28 Feb 2018
Cited by 380 | Viewed by 35183
Abstract
Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different [...] Read more.
Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different plants, herbs, whole grain products, processed foods (dark chocolate), as well as tea, coffee, and red wine. Polyphenols are believed to reduce morbidity and/or slow down the development of cardiovascular and neurodegenerative diseases as well as cancer. Biological activity of polyphenols is strongly related to their antioxidant properties. They tend to reduce the pool of reactive oxygen species as well as to neutralize potentially carcinogenic metabolites. A broad spectrum of health-promoting properties of plant polyphenols comprises antioxidant, anti-inflammatory, anti-allergic, anti-atherogenic, anti-thrombotic, and anti-mutagenic effects. Scientific studies present the ability of polyphenols to modulate the human immune system by affecting the proliferation of white blood cells, and also the production of cytokines or other factors that participate in the immunological defense. The aim of the review is to focus on polyphenols of olive oil in context of their biological activities. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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15 pages, 3041 KiB  
Review
The Molecular Mechanisms of Plant-Derived Compounds Targeting Brain Cancer
by Hueng-Chuen Fan, Ching-Shiang Chi, Yu-Kang Chang, Min-Che Tung, Shinn-Zong Lin and Horng-Jyh Harn
Int. J. Mol. Sci. 2018, 19(2), 395; https://doi.org/10.3390/ijms19020395 - 30 Jan 2018
Cited by 9 | Viewed by 4997
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and malignant forms of brain tumors. Despite recent advances in operative and postoperative treatments, it is almost impossible to perform complete resection of these tumors owing to their invasive and diffuse nature. Several natural [...] Read more.
Glioblastoma multiforme (GBM) is one of the most aggressive and malignant forms of brain tumors. Despite recent advances in operative and postoperative treatments, it is almost impossible to perform complete resection of these tumors owing to their invasive and diffuse nature. Several natural plant-derived products, however, have been demonstrated to have promising therapeutic effects, such that they may serve as resources for anticancer drug discovery. The therapeutic effects of one such plant product, n-butylidenephthalide (BP), are wide-ranging in nature, including impacts on cancer cell apoptosis, cell cycle arrest, and cancer cell senescence. The compound also exhibits a relatively high level of penetration through the blood-brain barrier (BBB). Taken together, its actions have been shown to have anti-proliferative, anti-chemoresistance, anti-invasion, anti-migration, and anti-dissemination effects against GBM. In addition, a local drug delivery system for the subcutaneous and intracranial implantation of BP wafers that significantly reduce tumor size in xenograft models, as well as orthotopic and spontaneous brain tumors in animal models, has been developed. Isochaihulactone (ICL), another kind of plant product, possesses a broad spectrum of pharmacological activities, including impacts on cancer cell apoptosis and cell cycle arrest, as well as anti-proliferative and anti-chemoresistance effects. Furthermore, these actions have been specifically shown to have cancer-fighting effects on GBM. In short, the results of various studies reviewed herein have provided substantial evidence indicating that BP and ICH are promising novel anticancer compounds with good potential for clinical applications. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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867 KiB  
Review
Antiangiogenic Effect of Flavonoids and Chalcones: An Update
by Ladislav Mirossay, Lenka Varinská and Ján Mojžiš
Int. J. Mol. Sci. 2018, 19(1), 27; https://doi.org/10.3390/ijms19010027 - 22 Dec 2017
Cited by 85 | Viewed by 6787
Abstract
Chalcones are precursors of flavonoid biosynthesis in plants. Both flavonoids and chalcones are intensively investigated because of a large spectrum of their biological activities. Among others, anticancer and antiangiogenic effects account for the research interest of these substances. Because of an essential role [...] Read more.
Chalcones are precursors of flavonoid biosynthesis in plants. Both flavonoids and chalcones are intensively investigated because of a large spectrum of their biological activities. Among others, anticancer and antiangiogenic effects account for the research interest of these substances. Because of an essential role in cancer growth and metastasis, angiogenesis is considered to be a promising target for cancer treatment. Currently used antiangiogenic agents are either synthetic compounds or monoclonal antibodies. However, there are some limitations of their use including toxicity and high price, making the search for new antiangiogenic compounds very attractive. Nowadays it is well known that several natural compounds may modulate basic steps in angiogenesis. A lot of studies, also from our lab, showed that phytochemicals, including polyphenols, are potent modulators of angiogenesis. This review paper is focused on the antiangiogenic effect of flavonoids and chalcones and discusses possible underlying cellular and molecular mechanisms. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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