Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 19, Issue 18, 2019

Breast cancer is too complex with various different molecular alterations involved in its pathogenesis and progression. Over the decade, we have seen a surge in the development of drugs for bimolecular targets and for the signal transduction pathways involved in the treatment line of breast cancer. These drugs, either alone or in combination with conventional treatments like chemotherapy, hormone therapy and radiotherapy, will help oncologists to get a better insight and do the needful treatment. These novel therapies bring various challenges along with them, which include the dosage selection, patient selection, schedule of treatment and weighing of clinical benefits over side effects. In this review, we highlight the recently studied target molecules that have received indications in breast carcinoma, both in the localized and in an advanced state and about their inhibitors which are in clinical development which can give the immense potential to clinical care in the near future.

Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.

Aim: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated. Methods: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement. Results: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression. Conclusion: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.

Background: Isothiocyanates (ITCs) are small molecules that are important in synthetic organic chemistry, but their actual importance lies in their potential as anti-carcinogens. Through this piece of work, an effort was made to assess the anti-cancer activity of some simple ITCs which can be synthesized through easy greener pathways. Methods: Cell proliferation assay was performed on ovarian cancer cells (PA-1) and non-tumorigenic ovarian epithelial cells (IOSE-364). Furthermore, qRT-PCR for transcript expression levels of Spindlin1 and caspases in ovarian cancer cells and cell cycle analysis was performed. In silico studies were incorporated to understand the mode of ligand-protein interaction, ADME/Toxicity and drug-likeliness parameters. Density functional theory studies have been also been employed on the ITCs to assess their efficiency in anticancer activity. Results: An inexpensive, environmentally benign pathway has been developed for synthesizing a series of ITCs. Among the synthesized ITCs, NC6 showed better cytotoxic effects as compared to its counterparts. Novel findings revealed that NC6 had 5-folds lower transcript expression levels of Spindlin1 and induced caspases 3 and 7 expressions assessed by qRT-PCR in ovarian cancer cells. Furthermore, flow cytometry assay showed the cell cycle arrest at G1/S phase of cell cycle. The molecular docking studies revealed favorable binding affinities and the physiochemical parameters were predicted to be compatible with drug-likeliness. Conclusion: The results demonstrated the possibility that small isothiocyanate molecules which can be synthesized by a simple green methodology, can pose as promising candidates for their application as anticancer agents.

Background: Coconut oil is an edible oil obtained from fresh, mature coconut kernels. Few studies have reported the anticancer role of coconut oil. The fatty acid component of coconut oil directly targets the liver by portal circulation and as chylomicron via lymph. However, the anti-cancer activity of coconut oil against liver cancer cells and oral cancer cells is yet to be tested. The active component of coconut oil, that is responsible for the anticancer activity is not well understood. In this study, three different coconut oils, Virgin Coconut Oil (VCO), Processed Coconut Oil (PCO) and Fractionated Coconut Oil (FCO), were used. Objective: Based on previous studies, it can be hypothesized that fatty acids in coconut oil may have anticancer potential and may trigger cell death in cancer cell lines. Methods: Each cell line was treated with different concentrations of Virgin Coconut Oil (VCO), Processed Coconut Oil (PCO) and Fractionated Coconut Oil (FCO). The treated cells were assayed by MTT after 72 hr of incubation. The fatty acid composition of different coconut oils was analyzed by gas chromatography. Result: Different concentrations of coconut oils were used to treat the cells. Interestingly, the anticancer efficacy of VCO, PCO and FCO was not uniform, rather the efficacy varied from cell line to cell line. Only 20% VCO showed significant anticancer activity in HepG2 cells in comparison to 80% PCO against the KB cell line. Remarkably, 20% of PCO and 5% of FCO showed potential growth inhibition in the KB cell line as compared to 80% PCO in HepG2 cells. Moreover, there was a difference in the efficacy of VCO, PCO and FCO, which might be due to their fatty acid composition. Comparing the anticancer efficacy of VCO, PCO and FCO in this study helped to predict which class of fatty acids and which fatty acid might be associated with the anticancer activity of VCO. Conclusion: This study shows that VCO, PCO and FCO have anticancer efficacy and may be used for the treatment of cancer, especially liver and oral cancer.

Objective: The objectives of this study were to investigate the effects of proliferation, apoptosis, cell cycle, invasion, and senescence of KW-2478 on HepG2 cells, and to explore the related mechanism of apoptosis and the cell cycle. Methods: HepG2 cells (hepatocellular carcinoma cells) were cultured with KW-2478, at different doses and for different times, in vitro. The MTT assay was used to detect the effect of KW-2478 on proliferation of HepG2 cells. Flow cytometry was used to determine the effects of KW-2478 on the cell cycle and apoptosis of HepG2 cells. The Transwell assay was used to determine the effect of KW-2478 on cell invasion. The β-galactosidase assay tested the effect of low-dose KW-2478 on the senescence of HepG2 cells. Western blotting and the quantitative polymerase chain reaction were used respectively to assess changes in protein and mRNA levels of related factors in HepG2 cells after the KW-2478 treatment. Results: KW-2478 significantly inhibited proliferation of HepG2 cells. KW-2478 induced apoptosis and cell cycle arrest of HepG2 cells, and inhibited the invasion of HepG2 cells; low dose KW-2478 promoted HepG2 senescence. Conclusion: KW-2478 inhibited the proliferation of HepG2 cells, induced apoptosis and cell cycle arrest, inhibited invasion, and promoted senescence. KW-2478 affected the expression of related factors in the mitochondrial apoptotic signaling and cell cycle-related regulatory pathways. KW-2478 downregulated the expression of STAT3, which is a key factor in the JAK-STAT pathway, indicating that KW-2478 may affect the function of HepG2 cells by downregulating STAT3.

Background & Objective: Ovarian cancer has the highest mortality in gynecological tumors without effective therapeutic drugs as a result of drug-resistance for long-term utilization. Morin has been reported to possess powerful anti-tumor effects in several cancers. The present study aims to investigate whether Morin could influence ovarian cancer growth and underlying mechanisms. Methods: Morin was administered to cultured cells in vitro and formed tumors in vivo. MTT and colony formation assays were performed to explore the effects of Morin on the proliferation and colony formation of OVCAR3 and SKOV3 ovarian cancer cells. Western blot, RT-qPCR, immunofluorescence as well as ELISA were used to detect protein and mRNA expression of target factors. Tumor formation was performed to investigate tumorigenesis ability of drug-treated cells. Results: The proliferation and colony size of OVCAR3 and SKOV3 were significantly decreased after Morin administration. The expression of NF-ΚB and inflammatory cytokine IL6/8 induced by TNF-α can be inhibited by Morin. Furthermore, Morin inhibited the volume of ovarian cancer tumors in nude mice. Conclusion: Morin effectively alleviates ovarian cancer growth, inhibits the inflammatory response, and reduces tumor size via modulation of the NF-ΚB pathway.

Background: Species of crocodiles and cockroaches can withstand high radiation, reside in unsanitary conditions, thrive on germ-infested feed, and are exposed to heavy metals, yet they are not reported to develop cancer. It has been postulated that such species have mechanisms to defend themselves against developing cancer. Here, selected species have been tested for potential cytotoxicity against selected cancer cell lines. Methods: In this study, various species of vertebrates and invertebrates were procured including Columba livia, Gallus gallus domesticus, Varanus salvator, Cuora kamamora amboinensis, Reticulatus malayanus, Oreochromis mossambicus, Rattus rattus, American bullfrog, Donax sp., Polymesoda coaxans, Tenebrio molitor, Lumbricus terrestris, Blatta lateralis, Grammostola rosea, and Penaeus monodon. Species were dissected and their organ lysates/sera/haemolymph were prepared. Cytotoxicity assays were performed using Prostate Cancer cells (PC3), Henrietta Lacks cervical adenocarcinoma cells (HeLa) and human breast adenocarcinoma cells (MCF7) as well as human keratinized skin cells (Hacat), by measuring lactate dehydrogenase release as an indicator for cell death. Growth inhibition assays were performed to determine the effects on cancer cell proliferation. Liquid Chromatography-Mass Spectrometry (LC-MS/MS) was performed for molecular identification. Results: The results revealed that body lysates of Polymesoda coaxans demonstrated more than 99% growth inhibition of all cancer cell lines tested but not on normal Hacat cells. More importantly, the serum of M. reticulatus abolished growth and produced cytotoxicity. Hence these samples were subjected to Liquid Chromatography- Mass Spectrometry (LC-MS/MS), which detected 81 small molecules and putatively identified 20 molecules when matched against the METLIN database. Out of 1094 peptides, 21 peptides were identified, while 1074 peptides were categorized as novel peptides. Based on properties such as peptide amino acid composition, binary profile, dipeptide composition and pseudo-amino acid composition, 306 potential peptides were identified. Conclusion: To our knowledge, here for the first time, we report a comprehensive analysis of sera exhibiting cytotoxicity against cancer cell lines tested and identified several molecules using LC-MS/MS.

Background: As involved in tumor angiogenesis, Neuropilin Receptor type-1 (NRP-1) serves as an attractive target for cancer molecular imaging and therapy. Widespread expression of NRP-1 in normal tissues may affect anti-NRP-1 antibody tumor uptake. Objective: To assess a novel anti-NRP-1 monoclonal antibody A6-11-26 biodistribution in NRP-1 positive tumor xenograft models to understand the relationships between dose, normal tissue uptake and tumor uptake. Methods: The A6-11-26 was radiolabeled with 131I and the mice bearing U87MG xenografts were then administered with 131I-labelled A6-11-26 along with 0, 2.5, 5, and 10mg·kg-1 unlabelled antibody A6-11-26. Biodistribution and SPECT/CT imaging were evaluated. Results: 131I-A6-11-26 was synthesized successfully by hybridoma within 60min. It showed that most of 131IA6- 11-26 were in the plasma and serum (98.5 ± 0.16 and 88.9 ± 5.84, respectively), whereas, less in blood cells. For in vivo biodistribution studies, after only injection of 131I-A6-11-26, high levels of radioactivity were observed in the liver, moderate level in lungs. However, liver and lungs radioactivity uptakes could be competitively blocked by an increasing amount of unlabeled antibody A6-11-26, which can increase tumor radioactivity levels, but not in a dose-dependent manner. A dose between 10 and 20mg·kg-1 of unlabeled antibody A6-11-26 may be the optimal dose that maximized tumor exposure. Conclusion: Widespread expression of NRP-1 in normal tissue may affect the distribution of A6-11-26 to tumor tissue. An appropriate antibody A6-11-26 dose would be required to saturate normal tissue antigenic sinks to achieve acceptable tumor exposure.