Role of Plant - derived Epigentic Inhibitor and its Nonoparticle Formulation in Cancer Therapy: An Involvement of Apoptotic Signalling Pathway Modulation

Abstract

ancer poses a major health issue of mankind to date. According to the survey conducted by GLOBOCAN, there were 17.0 million new cancer cases and 9.5 million deaths in 2018 worldwide. Conventional treatment approaches of cancer have several limitations like undesired toxicity, cancer resistance and recurrence of the disease. Epigenetic alteration followed by permanent mutation of genes involved in cell growth and apoptosis is the common hallmark of cancer. As the epigenetic changes are repairable, targeting the epigenetic mechanism is a novel strategy in cancer therapy. Thus, researchers are in quest of plant- derived epigenetic inhibitors which are safe to the human body and may induce apoptosis of cancer cells. Furthermore, biodegradable nanoparticles (NPs) have a prominent role in the targeted delivery of the bioactive molecules at the tumour site and their enhanced anticancer efficacy. The present study was initiated with the investigation of in vitro anticancer activity of two bioflavonoids silibinin (SBN) and quercetin (QCT) by evaluating cell viability, colony formation efficiency and apoptosis of human lung and breast cancer cell lines A549 and MDA-MB-468 respectively. The curative and preventive anticancer efficacy of SBN and QCT was carried out in cancer cell lines induced tumour xenograft model in C57BL6 mice. The role of SBN and QCT in triggering cellular apoptotic signalling pathway through modulating tumour suppressor gene (TSG) p53, proto-oncogene Bcl2 and superoxide dismutase (SOD) enzyme activity was explored. Preclinical oral toxicity study showed that the test compounds were safe to the C57BL6 mice. A novel formulation of QCT viz. QCT loaded chitosan nanoparticles (QCT-CS NPs) was prepared by ionic gelation method. The NPs were successfully characterized for size, polydispersity index (PDI), zeta potential, drug-polymer compatibility and stability. The formulation was tested for its in vitro and in vivo anticancer activity and exhibited improved efficacy as compared to free QCT. In addition, in vitro cell uptake and in vivo biodistribution study were performed using FITC loaded NPs. The result showed that the NPs were efficiently accumulated in the tumour tissue in comparison with other vital organs and rapidly internalized into the cancer cells. Furthermore, the systemic toxicity study exhibited that the developed formulation was well tolerated by the C57BL6 mice. Therefore, the present study concludes that SBN and QCT are promising candidates in preventing cancer through stimulating p53, Bcl2 and SOD mediated interlinked apoptotic signalling pathways. They may be consumed as routine dietary nutraceuticals to inhibit cancer growth and progression throughout our lifetime. Moreover, the novel formulation QCT-CS NPs may efficiently deliver QCT at the tumour site and improve its chemopreventive efficacy.