Current Cancer Drug Targets - Volume 19, Issue 2, 2019

Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.

Malignant high-grade glioma (HGG) is the most common and extremely fatal type of primary intracranial tumor. These tumors recurred within 2 to 3 cm of the primary region of tumor resection in the majority of cases. Furthermore, the blood-brain barrier significantly limited the access of many systemically administered chemotherapeutics to the tumor, pointing towards a stringent need for new therapeutic patterns. Therefore, targeting therapy using local drug delivery for HGG becomes a priority for the development of novel therapeutic strategies. The main objectives to the effective use of chemotherapy for HGG include the drug delivery to the tumor region and the infusion of chemotherapeutic agents into the vascular supply of a tumor directly, which could improve the pharmacokinetic profile by enhancing drug delivery to the neoplasm tissue. Herein, we reviewed clinical and molecular features, different methods of chemotherapy application in HGGs, especially the existing and promising targeting therapies using local drug delivery for HGG which could effectively inhibit tumor invasion, proliferation and recurrence of HGG to combat the deadly disease. Undoubtedly, novel chemical medicines targeting these HGG may represent one of the most important directions in the Neuro-oncology.

Recently, the chemotherapeutic drug-induced cellular senescence has been considered a promising anti-cancer approach. The drug-induced senescence, which shows both similar and different hallmarks from replicative and oncogene-induced senescence, was regarded as a key determinant of tumor response to chemotherapy in vitro and in vivo. To date, an amount of effective chemotherapeutic drugs that can evoke senescence in cancer cells have been reported. The targets of these drugs differ substantially, including senescence signaling pathways, DNA replication process, DNA damage pathways, epigenetic modifications, microtubule polymerization, senescence-associated secretory phenotype (SASP), and so on. By summarizing senescence-inducing small molecule drugs together with their specific traits and corresponding mechanisms, this review is devoted to inform scientists to develop novel therapeutic strategies against cancer through inducing senescence.

The widespread emergence of cancer and development of resistance to chemotherapeutic agents is increasing the interest of scientists in the use of ethnomedicinal preparations and isolated phytochemicals in the treatment and prevention of disease. Medicinal plants have been used in Pakistan since prehistoric times. The present review was designed to identify anticancer plants of ethnomedicinal significance and to summarize the anticancer activities carried out on these medicinal plants to establish the pharmacological and phytochemical basis of their use. Pakistani anticancer medicinal plants of ethnopharmacological significance were reviewed. Conservation status, worldwide distribution and ethno-botanical preparations of these medicinal plants were also tabulated. These medicinal plants and their isolated phytochemicals were also explored for their anticancer activities. It was revealed that there were 108 anticancer medicinal plants used to treat different neoplastic conditions on the folklore basis throughout Pakistan. Among these anticancer plants, 64 plants were found to be investigated previously for anticancer activity through in vivo and in vitro methods. Several ethnomedicinal plants have been validated for their anticancer activities through in vitro and animal models. These medicinal plants and phytochemicals resulted in the inhibition of initiation, progression or metastasis of neoplasm. Some medicinal plants (10) are endangered species. Half of folkloric Pakistani plants have been validated for use against various cancers through in vitro or in vivo methods. It is necessary to carry out further pharmacological and toxicological evaluation of these folkloric anticancer plants of Pakistan. It is also necessary to identify and isolate further potential phytochemicals so as to be evaluated in cancer patients.

Background: Cordycepin is a small molecule from medicinal mushroom Cordyceps, which has been reported for anticancer properties. Objective: In this study, we have focused on the investigation of cordycepin effect on cervical cancer cells with further clarification of possible molecular mechanism. Method: We have used cell viability and cell counting assay for cytotoxic effect of cordycepin, flow cytometric assay of apoptosis and cell cycle, and quantitative PCR (qPCR) and Western blotting for the determination of target gene expression. Molecular docking and Molecular dynamics simulation were used for in silico analysis of cordycepin affinity to target protein(s). Results: Treatment of cordycepin controlled SiHa and HeLa cervical cancer cell growth, increased the rate of their apoptosis, and interfered with cell cycle, specifically elongated S-phase. qPCR results indicated that there was a downregulation of cell cycle proteins CDK-2, CYCLIN-A2 and CYCLIN-E1 in mRNA level by cordycepin treatment but no significant change was observed in pro-apoptotic or antiapoptotic proteins. The intracellular reactive oxygen species (ROS) level in cordycepin treated cells was increased significantly, implying that apoptosis might be induced by ROS. Western blot analysis confirmed significant decrease of Cdk-2 and mild decrease of Cyclin-E1 and Cyclin-A2 by cordycepin, which might be responsible for regulating cell cycle. Molecular docking indicated high binding affinity of cordycepin against Cdk-2. Molecular dynamics simulation further confirmed that the docked pose of cordycepin-Cdk-2 complex remained within the binding pocket for 10 ns. Conclusion: Our study suggests that cordycepin is effective against cervical cancer cells, and regulating cell cycle via cell cycle proteins, especially downregulating Cdk-2, and inducing apoptosis by generating ROS are among the mechanisms of anticancer activities of cordycepin.