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27 pages, 6098 KiB

Open AccessArticle

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

by Andrey V. Markov, Kirill V. Odarenko, Aleksandra V. Sen’kova, Oksana V. Salomatina, Nariman F. Salakhutdinov and Marina A. Zenkova

Molecules 2020, 25(24), 5925; https://doi.org/10.3390/molecules25245925 - 14 Dec 2020

Cited by 8 | Viewed by 2745

Abstract

Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. [...] Read more.

Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. Further study showed that SM effectively blocked transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-β-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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11 pages, 2613 KiB

Open AccessArticle

Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells

by Keun-Yeong Jeong, Minhee Park, Jae-Jun Sim and Hwan Mook Kim

Molecules 2020, 25(22), 5299; https://doi.org/10.3390/molecules25225299 - 13 Nov 2020

Cited by 11 | Viewed by 2175

Abstract

Sorafenib has been recently used for the treatment of patients with advanced colorectal cancer (CRC) and is recognized for its therapeutic value. However, the continuous use of sorafenib may cause resistance in the treatment of cancer patients. In this study, we investigated whether [...] Read more.

Sorafenib has been recently used for the treatment of patients with advanced colorectal cancer (CRC) and is recognized for its therapeutic value. However, the continuous use of sorafenib may cause resistance in the treatment of cancer patients. In this study, we investigated whether sorafenib exerts an enhanced anticancer effect on CRC cells via the calcium-mediated deactivation of the focal adhesion kinase (FAK) signaling pathways. The appropriate dose of sorafenib and lactate calcium salt (CaLa) for a combination treatment were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Then, cell cycle analysis was performed following treatment with 2.5 μM sorafenib and/or 2.5 mM CaLa. CRC cells were found to be in the G1 phase by sorafenib treatment, and they accumulated in the sub-G1 phase with CaLa treatment. Western blots and enzyme-linked immunosorbent assays were performed to analyze the elements of the recombinant activated factor (RAF) and focal adhesion kinase (FAK) signaling cascades. Sorafenib-inhibited RAF-dependent signaling in CRC cells, however, either did not affect the expression of Akt or increased it. As the upstream signaling of FAK was suppressed by CaLa, we observed that the expression of the sub-signaling phospho (p) AKT and p-mammalian target of rapamycin was also suppressed. Treatment with a combination of sorafenib and CaLa enhanced the antitumor activity of CRC cells. The % viability of CRC cells was significantly decreased compared to the single treatment with sorafenib or CaLa, and the accumulation of Sub G1 of CRC cells was clearly confirmed. The migration ability of CRC cells was significantly reduced. The findings of this study indicate that sorafenib will show further improved antitumor efficacy against CRC due to overcoming resistance through the use of CaLa. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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26 pages, 2666 KiB

Open AccessArticle

Antitumor, Immunomodulatory and Antiangiogenic Efficacy of Medicinal Mushroom Extract Mixtures in Advanced Colorectal Cancer Animal Model

by Boris Jakopovic, Nada Oršolić and Sandra Kraljević Pavelić

Molecules 2020, 25(21), 5005; https://doi.org/10.3390/molecules25215005 - 28 Oct 2020

Cited by 15 | Viewed by 5601

Abstract

Due to frequent drug resistance and/or unwanted side-effects during conventional and targeted cancer treatments, development of multi-target therapies is an important research field. Medicinal mushrooms’ isolated specific compounds and mushroom extracts have been already proven as non-toxic multi-target inhibitors of specific oncogenic pathways, [...] Read more.

Due to frequent drug resistance and/or unwanted side-effects during conventional and targeted cancer treatments, development of multi-target therapies is an important research field. Medicinal mushrooms’ isolated specific compounds and mushroom extracts have been already proven as non-toxic multi-target inhibitors of specific oncogenic pathways, as well as potent immunomodulators. However, research on antitumor effects of multiple-species extract mixtures was limited so far. The aim of this study was therefore, a study of medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS on colorectal cell lines in vitro and colorectal mice model in vivo. We found a significant antiproliferative and pro-apoptotic effect of tested medicinal mushroom preparations on colorectal (HCT-116, SW620) tumor cell lines, while the effect on human fibroblast cell line (WI-38) was proliferative emphasizing a specificity towards tumor cell lines. We further investigated the effect of the medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS in various combinations with conventional cytostatic drug 5-fluorouracil in the advanced metastatic colorectal cancer mouse model CT26.WT. AGARIKON.1 and AGARIKON PLUS exhibited immunostimulatory and antiangiogenic properties in vivo which resulted in significantly increased survival and reduction in tumor volume. The antitumor effects of AGARIKON.1 and AGARIKON PLUS, with or without 5-fluorouracil, are based on M1 macrophage polarization enhancement, inhibition of M2 and tumor-associated macrophage (TAM) polarization, effects on T helper cell Th1/Th2/Th17 cytokine profiles, direct inhibition of CT26.WT tumor growth, inhibition of vascular endothelial growth factors (VEGF) and metalloproteinases 2 and 9 (MMP-2 and MMP-9) modulation. The administration of AGARIKON.1 and AGARIKON PLUS did not show genotoxic effect. This data provides good basis for an expanded translational study. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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13 pages, 2910 KiB

Open AccessArticle

Investigation of Dextran-Coated Superparamagnetic Nanoparticles for Targeted Vinblastine Controlled Release, Delivery, Apoptosis Induction, and Gene Expression in Pancreatic Cancer Cells

by Salim Albukhaty, Sharafaldin Al-Musawi, Salih Abdul Mahdi, Ghassan M. Sulaiman, Mona S. Alwahibi, Yaser Hassan Dewir, Dina A. Soliman and Humaira Rizwana

Molecules 2020, 25(20), 4721; https://doi.org/10.3390/molecules25204721 - 15 Oct 2020

Cited by 51 | Viewed by 3643

Abstract

In the current study, the surface of superparamagnetic iron oxide (SPION) was coated with dextran (DEX), and conjugated with folic acid (FA), to enhance the targeted delivery and uptake of vinblastine (VBL) in PANC-1 pancreatic cancer cells. Numerous analyses were performed to validate [...] Read more.

In the current study, the surface of superparamagnetic iron oxide (SPION) was coated with dextran (DEX), and conjugated with folic acid (FA), to enhance the targeted delivery and uptake of vinblastine (VBL) in PANC-1 pancreatic cancer cells. Numerous analyses were performed to validate the prepared FA-DEX-VBL-SPION, such as field emission scanning transmission electron microscopy, high-resolution transmission electron microscopy, dynamic light scattering (DLS), Zeta Potential, Fourier transform infrared spectroscopy, and vibrating sample magnetometry (VSM). The delivery system capacity was evaluated by loading and release experiments. Moreover, in vitro biological studies, including a cytotoxicity study, cellular uptake assessment, apoptosis analysis, and real-time PCR, were carried out. The results revealed that the obtained nanocarrier was spherical with a suitable dispersion and without visible aggregation. Its average size, polydispersity, and zeta were 74 ± 13 nm, 0.080, and −45 mV, respectively. This dual functional nanocarrier also exhibited low cytotoxicity and a high apoptosis induction potential for successful VBL co-delivery. Real-time quantitative PCR analysis demonstrated the activation of caspase-3, NF-1, PDL-1, and H-ras inhibition, in PANC-1 cells treated with the FA-VBL-DEX-SPION nanostructure. Close inspection of the obtained data proved that the FA-VBL-DEX-SPION nanostructure possesses a noteworthy chemo-preventive effect on pancreatic cancer cells through the inhibition of cell proliferation and induction of apoptosis. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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13 pages, 259 KiB

Open AccessArticle

ZeOxaNMulti Trial: A Randomized, Double-Blinded, Placebo-Controlled Trial of Oral PMA-Zeolite to Prevent Chemotherapy-Induced Side Effects, in Particular, Peripheral Neuropathy

by Maria Giuseppa Vitale, Carmela Barbato, Anna Crispo, Francesco Habetswallner, Bernardo Maria De Martino, Ferdinando Riccardi, Angela Maione, Sandra Eisenwagen, Giovanna Vitale and Giacomo Cartenì

Molecules 2020, 25(10), 2297; https://doi.org/10.3390/molecules25102297 - 13 May 2020

Cited by 11 | Viewed by 4149

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible impact of the PMA-zeolite as an adjuvant therapeutic agent is based on its detoxification properties toward agents promoting the development of neuropathy (e.g., ammonium—recognized as a neurotoxic agent produced by tumors), as well as its positive impact on immunity and oxidative stress through its effects in the gastrointestinal tract. From April 2015 to October 2018, a total of 120 patients (pts) diagnosed with predominantly colorectal cancer requiring oxaliplatin-based chemotherapy were randomized to receive either the PMA-zeolite (Multizeo Med) or placebo while undergoing oxaliplatin-based chemotherapy. A nerve-conduction study (NCS) was planned at the baseline, after three and six months of chemotherapy, to evaluate CIPN. Furthermore, the evaluation of hematological and liver toxicity was performed during every cycle of chemotherapy. 70.6% and 64.3% of patients developed CIPN in the placebo and the PMA-zeolite group, respectively. Patients treated with the PMA-zeolite were able to undergo more cycles of chemotherapy (p = 0.03), which also indicates a significant improvement in tolerance to the therapy. The group treated with the PMA-zeolite showed a lower CIPN (although not statistically significant within the whole group of subjects) compared to patients receiving placebo. This advantage was, however, statistically significant in men (p = 0.047). In addition, supplementation with the PMA-zeolite resulted in a lower incidence of severe-grade hematological toxicity (trend toward statistical significance of p = 0.09 was observed). Cancer patients may benefit from the therapy with the appropriate certified zeolite-products (e.g., the PMA-zeolite) for human use in CIPN. The lower CIPN (statistically significant results in the male subgroup) was accompanied by a trend of lower incidence of severe-grade hematological toxicity. Furthermore, these benefits led to a better tolerance toward chemotherapy (increase in cycles) and allow an improved compliance with the oncological treatment protocol. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

24 pages, 15962 KiB

Open AccessFeature PaperArticle

Purine and Purine Isostere Derivatives of Ferrocene: An Evaluation of ADME, Antitumor and Electrochemical Properties

by Valentina Rep, Martina Piškor, Helena Šimek, Petra Mišetić, Petra Grbčić, Jasna Padovan, Vesna Gabelica Marković, Dijana Jadreško, Krešimir Pavelić, Sandra Kraljević Pavelić and Silvana Raić-Malić

Molecules 2020, 25(7), 1570; https://doi.org/10.3390/molecules25071570 - 29 Mar 2020

Cited by 12 | Viewed by 3732

Abstract

Novel purine and purine isosteres containing a ferrocene motif and 4,1-disubstituted (11a−11c, 12a−12c, 13a−13c, 14a−14c, 15a−15c, 16a, 23a−23c, 24a−24c, 25a [...] Read more.

Novel purine and purine isosteres containing a ferrocene motif and 4,1-disubstituted (11a−11c, 12a−12c, 13a−13c, 14a−14c, 15a−15c, 16a, 23a−23c, 24a−24c, 25a−25c) and 1,4-disubstituted (34a−34c and 35a−35c) 1,2,3-triazole rings were synthesized. The most potent cytotoxic effect on colorectal adenocarcinoma (SW620) was exerted by the 6-chloro-7-deazapurine 11c (IC₅₀ = 9.07 µM), 6-chloropurine 13a (IC₅₀ = 14.38 µM) and 15b (IC₅₀ = 15.50 µM) ferrocenylalkyl derivatives. The N-9 isomer of 6-chloropurine 13a containing ferrocenylmethylene unit showed a favourable in vitro physicochemical and ADME properties including high solubility, moderate permeability and good metabolic stability in human liver microsomes. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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32 pages, 9196 KiB

Open AccessArticle

Chemopreventive and Therapeutic Efficacy of Cinnamomum zeylanicum L. Bark in Experimental Breast Carcinoma: Mechanistic In Vivo and In Vitro Analyses

by Peter Kubatka, Martin Kello, Karol Kajo, Marek Samec, Karin Jasek, Desanka Vybohova, Sona Uramova, Alena Liskova, Vladimira Sadlonova, Lenka Koklesova, Radovan Murin, Marian Adamkov, Karel Smejkal, Emil Svajdlenka, Peter Solar, Samson Mathews Samuel, Monika Kassayova, Taeg Kyu Kwon, Pavol Zubor, Martin Pec, Jan Danko, Dietrich Büsselberg and Jan Mojzis Show full author list Hide full author list

Molecules 2020, 25(6), 1399; https://doi.org/10.3390/molecules25061399 - 19 Mar 2020

Cited by 46 | Viewed by 6203

Abstract

Comprehensive oncology research suggests an important role of phytochemicals or whole plant foods in the modulation of signaling pathways associated with anticancer action. The goal of this study is to assess the anticancer activities of Cinnamomum zeylanicum L. using rat, mouse, and cell [...] Read more.

Comprehensive oncology research suggests an important role of phytochemicals or whole plant foods in the modulation of signaling pathways associated with anticancer action. The goal of this study is to assess the anticancer activities of Cinnamomum zeylanicum L. using rat, mouse, and cell line breast carcinoma models. C. zeylanicum (as bark powder) was administered in the diet at two concentrations of 0.1% (w/w) and 1% (w/w) during the whole experiment in chemically induced rat mammary carcinomas and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular evaluations of mammary gland tumors in rodents were carried out. Moreover, in vitro analyses using MCF-7 and MDA-MB-231 cells were performed. The dominant metabolites present in the tested C. zeylanicum essential oil (with relative content over 1%) were cinnamaldehyde, cinnamaldehyde dimethyl acetal, cinnamyl acetate, eugenol, linalool, eucalyptol, limonene, o-cymol, and α-terpineol. The natural mixture of mentioned molecules demonstrated significant anticancer effects in our study. In the mouse model, C. zeylanicum at a higher dose (1%) significantly decreased tumor volume by 44% when compared to controls. In addition, treated tumors showed a significant dose-dependent decrease in mitotic activity index by 29% (0.1%) and 45.5% (1%) in comparison with the control group. In rats, C. zeylanicum in both doses significantly reduced the tumor incidence by 15.5% and non-significantly suppressed tumor frequency by more than 30% when compared to controls. An evaluation of the mechanism of anticancer action using valid oncological markers showed several positive changes after treatment with C. zeylanicum. Histopathological analysis of treated rat tumor specimens showed a significant decrease in the ratio of high-/low-grade carcinomas compared to controls. In treated rat carcinomas, we found caspase-3 and Bax expression increase. On the other hand, we observed a decrease in Bcl-2, Ki67, VEGF, and CD24 expressions and MDA levels. Assessment of epigenetic changes in rat tumor cells in vivo showed a significant decrease in lysine methylation status of H3K4m3 and H3K9m3 in the high-dose treated group, a dose-dependent increase in H4K16ac levels (H4K20m3 was not changed), down-regulations of miR21 and miR155 in low-dose cinnamon groups (miR22 and miR34a were not modulated), and significant reduction of the methylation status of two out of five gene promoters—ATM and TIMP3 (PITX2, RASSF1, PTEN promoters were not changed). In vitro study confirmed results of animal studies, in that the essential oil of C. zeylanicum displayed significant anticancer efficacy in MCF-7 and MDA-MB-231 cells (using MTS, BrdU, cell cycle, annexin V/PI, caspase-3/7, Bcl-2, PARP, and mitochondrial membrane potential analyses). As a conclusion, C. zeylanicum L. showed chemopreventive and therapeutic activities in animal breast carcinoma models that were also significantly confirmed by mechanistic evaluations in vitro and in vivo. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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Review

Jump to: Research

43 pages, 2119 KiB

Open AccessReview

Antitumor Drugs and Their Targets

by Zlatko Dembic

Molecules 2020, 25(23), 5776; https://doi.org/10.3390/molecules25235776 - 7 Dec 2020

Cited by 44 | Viewed by 8424

Abstract

Through novel methodologies, including both basic and clinical research, progress has been made in the therapy of solid cancer. Recent innovations in anticancer therapies, including immune checkpoint inhibitor biologics, therapeutic vaccines, small drugs, and CAR-T cell injections, mark a new epoch in cancer [...] Read more.

Through novel methodologies, including both basic and clinical research, progress has been made in the therapy of solid cancer. Recent innovations in anticancer therapies, including immune checkpoint inhibitor biologics, therapeutic vaccines, small drugs, and CAR-T cell injections, mark a new epoch in cancer research, already known for faster (epi-)genomics, transcriptomics, and proteomics. As the long-sought after personalization of cancer therapies comes to fruition, the need to evaluate all current therapeutic possibilities and select the best for each patient is of paramount importance. This is a novel task for medical care that deserves prominence in therapeutic considerations in the future. This is because cancer is a complex genetic disease. In its deadly form, metastatic cancer, it includes altered genes (and their regulators) that encode ten hallmarks of cancer-independent growth, dodging apoptosis, immortalization, multidrug resistance, neovascularization, invasiveness, genome instability, inflammation, deregulation of metabolism, and avoidance of destruction by the immune system. These factors have been known targets for many anticancer drugs and treatments, and their modulation is a therapeutic goal, with the hope of rendering solid cancer a chronic rather than deadly disease. In this article, the current therapeutic arsenal against cancers is reviewed with a focus on immunotherapies. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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29 pages, 1810 KiB

Open AccessReview

Implementing Curcumin in Translational Oncology Research

by Koraljka Gall Trošelj, Ivana Samaržija, Marko Tomljanović, Renata Novak Kujundžić, Nikola Đaković and Anamarija Mojzeš

Molecules 2020, 25(22), 5240; https://doi.org/10.3390/molecules25225240 - 10 Nov 2020

Cited by 11 | Viewed by 4940

Abstract

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a [...] Read more.

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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20 pages, 3305 KiB

Open AccessReview

Small Molecules Targeting Biological Clock; A Novel Prospective for Anti-Cancer Drugs

by Sadia Rahman, Karlo Wittine, Mirela Sedić and Elitza P. Markova-Car

Molecules 2020, 25(21), 4937; https://doi.org/10.3390/molecules25214937 - 26 Oct 2020

Cited by 11 | Viewed by 4296

Abstract

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body [...] Read more.

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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20 pages, 4040 KiB

Open AccessReview

Present and Future of Anti-Glioblastoma Therapies: A Deep Look into Molecular Dependencies/Features

by Hyeon Ji Kim and Do-Yeon Kim

Molecules 2020, 25(20), 4641; https://doi.org/10.3390/molecules25204641 - 12 Oct 2020

Cited by 9 | Viewed by 2310

Abstract

Glioblastoma (GBM) is aggressive malignant tumor residing within the central nervous system. Although the standard treatment options, consisting of surgical resection followed by combined radiochemotherapy, have long been established for patients with GBM, the prognosis is still poor. Despite recent advances in diagnosis, [...] Read more.

Glioblastoma (GBM) is aggressive malignant tumor residing within the central nervous system. Although the standard treatment options, consisting of surgical resection followed by combined radiochemotherapy, have long been established for patients with GBM, the prognosis is still poor. Despite recent advances in diagnosis, surgical techniques, and therapeutic approaches, the increased patient survival after such interventions is still sub-optimal. The unique characteristics of GBM, including highly infiltrative nature, hard-to-access location (mainly due to the existence of the blood brain barrier), frequent and rapid recurrence, and multiple drug resistance mechanisms, pose challenges to the development of an effective treatment. To overcome current limitations on GBM therapy and devise ideal therapeutic strategies, efforts should focus on an improved molecular understanding of GBM pathogenesis. In this review, we summarize the molecular basis for the development and progression of GBM as well as some emerging therapeutic approaches. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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21 pages, 2121 KiB

Open AccessReview

Sphingosine 1-Phosphate Signaling and Metabolism in Chemoprevention and Chemoresistance in Colon Cancer

by Petra Grbčić and Mirela Sedić

Molecules 2020, 25(10), 2436; https://doi.org/10.3390/molecules25102436 - 23 May 2020

Cited by 16 | Viewed by 4268

Abstract

Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process [...] Read more.

Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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15 pages, 1125 KiB

Open AccessReview

Nutraceuticals and Metastasis Development

by Lara Saftić Martinović, Željka Peršurić and Krešimir Pavelić

Molecules 2020, 25(9), 2222; https://doi.org/10.3390/molecules25092222 - 8 May 2020

Cited by 2 | Viewed by 2819

Abstract

Nutrigenomics is a discipline that studies the effects of various dietary components on gene expression and molecular mechanisms via “omics” technologies. Many studies are focused on revealing the pathways of the anticancer properties of various nutraceuticals. However, it has been shown that metastasis, [...] Read more.

Nutrigenomics is a discipline that studies the effects of various dietary components on gene expression and molecular mechanisms via “omics” technologies. Many studies are focused on revealing the pathways of the anticancer properties of various nutraceuticals. However, it has been shown that metastasis, a multifactorial disease that develops from primary tumors in cascades, is responsible for almost 90% of cancer deaths. Regrettably, the effects of consumption of different nutraceuticals on metastasis development have not yet been sufficiently explored. A few studies on the subject have revealed the promotional effects of some nutraceuticals on metastasis development. Additionally, it has been shown that certain compounds can have beneficial effects on reduction of the primary tumor, but afterwards promote the spread of metastases. Therefore, in this review we discuss results published in the past five years focused on the effects of different nutraceuticals on metastasis development. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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26 pages, 3741 KiB

Open AccessReview

Secondary Metabolites from Gorgonian Corals of the Genus Eunicella: Structural Characterizations, Biological Activities, and Synthetic Approaches

by Dario Matulja, Maria Kolympadi Markovic, Gabriela Ambrožić, Sylvain Laclef, Sandra Kraljević Pavelić and Dean Marković

Molecules 2020, 25(1), 129; https://doi.org/10.3390/molecules25010129 - 28 Dec 2019

Cited by 8 | Viewed by 4731

Abstract

Gorgonian corals, which belong to the genus Eunicella, are known as natural sources of diverse compounds with unique structural characteristics and interesting bioactivities both in vitro and in vivo. This review is focused primarily on the secondary metabolites isolated from various Eunicella [...] Read more.

Gorgonian corals, which belong to the genus Eunicella, are known as natural sources of diverse compounds with unique structural characteristics and interesting bioactivities both in vitro and in vivo. This review is focused primarily on the secondary metabolites isolated from various Eunicella species. The chemical structures of 64 compounds were divided into three main groups and comprehensively presented: a) terpenoids, b) sterols, and c) alkaloids and nucleosides. The observed biological activities of depicted metabolites with an impact on cytotoxic, anti-inflammatory, and antimicrobial activities were reviewed. The most promising biological activities of certain metabolites point to potential candidates for further development in pharmaceutical, cosmetic, and other industries, and are highlighted. Total synthesis or the synthetic approaches towards the desired skeletons or natural products are also summarized. Full article

(This article belongs to the Special Issue Translational Approach to Antitumor Drugs)

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