Anticancer effect of 7-hydroxycoumarin in cisplatin-resistant ovarian cancer cell is mediated via apoptosis induction, caspase activation and cell cycle arrest at G2M phase

Purpose: To investigate the anticancer effects of 7-hydroxycoumarin against cisplatin-resistant ovarian cancer cell line, and the underlying mechanism(s). Methods: Cell proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The 4’,6-diamidino-2-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) dual staining methods were used for measuring cell apoptosis in terms of DNA damage. Flow cytometry was used for analysis of mitosis of cancer cells, while protein expression levels were assayed with western blotting. Results: The 7-hydroxycoumarin preferentially inhibited the proliferation of the ovarian cancer cells, but had significantly less prominent effects on normal cells (p < 0.05). The decrease in cell proliferation was due to induction of cell apoptosis via caspase-linked apoptotic pathway. Treatment with 7- hdoxycoumarin further led to the arrest of cancer cell cycle at G2/M stage (p < 0.05) via down-regulation of the expressions of regulatory proteins that promote mitotic entry. Conclusion: 7-Hydroxycoumarin exerts significant anticancer effect against cisplatin-resistant ovarian cancer cells via decrease in cell proliferation, induction of apoptosis and mitotic cell cycle arrest. Thus, the compound could emerge as a vital lead molecule in the treatment of cisplatin-resistant type of human ovarian cancer.

Melatonin Induces Cell Cycle Arrest, Inhibits Cell Proliferation and Accelerates Apoptosis by Modulation of CDK4 in NSCLC

Purpose To explore whether melatonin affect the progression of cell cycle and exert anticancer activities via the modulation of CDK4 in NSCLC . Methods Cells treated with melatonin were used for assessing the anticancer effect of melatonin. Cells transfected with lentivirus for CDK4 upregulation or downregulation was constructed to evaluate the role of CDK4 in melatonin-induced anticancer effect. The protein and mRNA level of CDK4, PCNA and Bax were detected by western blotting and qRT-PCR. The application of flow cytometry was used for analyzing the distribution of cell cycle and apoptosis. Animal model of subcutaneous tumor was constructed and used for further study in vivo. Results We found that melatonin inhibited cell viability, colony formation, downregulated the expression of CDK4 and PCNA while upregulated the level of Bax. Besides, melatonin decreased the phosphorylation of ERK. Importantly, inhibition of ERK activation by PD98059 particapated in melatonin-induced downregulation of CDK4. Furthermore, melatonin led to G1 arrest and cell apoptosis. CDK4 knockdown enhanced melatonin-induced cell cycle arrest while CDK4 overexpression reversed the effect. Additionally, the animal experiment showed that melatonin decreased the level of CDK4 and inhibited tumor growth. However, the anti-tumor effect of melatonin was reversed by CDK4 overexpression. Conclusion Taken together, CDK4 involved in anti-cancer activities of melatonin. Melatonin led to G1 arrest, blocked G1-to-S transition, as a result, inhibited cell proliferation and accelerates apoptosis via suppressing CDK4 signaling. Targeting CDK4 inhibition and combining it with melatonin has protential to be a novel strategy for NSCLC.

Prospects of Curcumin Nanoformulations in Cancer Management

There is increasing interest in the use of natural compounds with beneficial pharmacological effects for managing diseases. Curcumin (CUR) is a phytochemical that is reportedly effective against some cancers through its ability to regulate signaling pathways and protein expression in cancer development and progression. Unfortunately, its use is limited due to its hydrophobicity, low bioavailability, chemical instability, photodegradation, and fast metabolism. Nanoparticles (NPs) are drug delivery systems that can increase the bioavailability of hydrophobic drugs and improve drug targeting to cancer cells via different mechanisms and formulation techniques. In this review, we have discussed various CUR-NPs that have been evaluated for their potential use in treating cancers. Formulations reviewed include lipid, gold, zinc oxide, magnetic, polymeric, and silica NPs, as well as micelles, dendrimers, nanogels, cyclodextrin complexes, and liposomes, with an emphasis on their formulation and characteristics. CUR incorporation into the NPs enhanced its pharmaceutical and therapeutic significance with respect to solubility, absorption, bioavailability, stability, plasma half-life, targeted delivery, and anticancer effect. Our review shows that several CUR-NPs have promising anticancer activity; however, clinical reports on them are limited. We believe that clinical trials must be conducted on CUR-NPs to ensure their effective translation into clinical applications.

Drug Repurposing of Asparaginase and Vitamin C Targeting Glutamine Synthetase Improves Anticancer Effect in Metastatic Castration-resistant Prostate Cancer

Background: Although in North America or Europe early dignosis of prostate cancer could sucessfully improves the therapeutic outcome. However, about 70-80% of patients still suffer from metastatic castration-resistant prostate cancer (mCRPC), because of the disproportionate medical care in China. Lutetium-177 (Lu-177) or Radium-223 (Ra-223) has been suggested as the most effective therapy for mCRPC. Unfortunately, they are either not been approved in a few countries or too expensive for patients with the financial issue. Drug repurposing has been recognized as a cost-effective and relatively low-risk alternative, gains a lot interesting recently. In this study, we explored the combined treatment with asparaginase (ASNase) and/or vitamin Cas an alternative therapeutic option for mCRPC management.Methods: Prostate cancer cell lines PC3 and DU145 were used to observe the therapeutic effect of ASNase and/or vitamin C on mCRPC in vitro and in vivo. Change of cell proliferation, cell death as well as expression of glutamine synthetase eunder different treatment conditions were detected to analyzed anticancer effect of combined therapy with ASNase and vitamin C on mCRPC. Intracellular oxidation was also observed with NADPH and NADP+ assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to vitamin C with or without ASNase through tumor growth, small animal PET/CT scans as well as Immunohistochemistry in vivo.Results: Our in vitro studies demonstrate that ASNase synergizes with vitamin C targeting expression of glutamine synthetase enhances redox imbalance and induces anticancer effect in mCRPC cells through regulation the glutamine synthetase (GS) expression. In vivo, combination of ASnase and vitamin C could provide a significant better therapeutic outcome in comparison with controls or single treated mice. 18F-FDG PET imaging illustrated that the treatment with combined therapy could significantly reduce the 18F-FDG uptake in tumor.Conclusions: In this current study, we suggest that ASNase combined with vitamin C could be as a cost-effective strategy to manage mCRPC.18F-FDG PET/CT imaging could indicate the therapeutic response of treatment for mCRPC.

Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.

Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice

In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1’s mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni’s tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg−1 once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra in-vivo experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1’s efficacy in various xenograft and/or syngeneic models.