Executive Summary : | Cancer is a multi-factorial set of diseases typically governed by the exponential and uncontrolled cell proliferation. In India, according to the latest report of ICMR-NCRP 2021, a total of 13,32,207 cancer cases were reported from 96 Hospital Based Cancer Registries (HBCRs) with 51% cases of breast cancer followed by lung and colon cancer. Different targets including vascular endothelial growth factor, histone deacetylase, caspase etc. are under investigation for their probable use as drugs. Out of the pool, targets which are specifically overexpressed in cancer cells serve as promising tool for developing selective therapeutic drug. My work at Bhabha Atomic Research Centre, Maharashtra, Mumbai, identified mitogen activated protein kinase phosphatase-1 (MKP-1), family tyrosine phosphatase, as a promising target for developing selective anticancer drugs. Several studies highlighted the key role of MKP-1 in cancer oncogenesis, tumorigenicity and metastasis. MKP-1 is overexpressed in more than 10 cancer types including colon, pancreatic, breast, prostate and gastric cancer. MKP-1 is accountable for dephosphorylation of phospho-tyrosine and phospho-threonine residues on JNK, P38 and ERK. Overexpression of MKP-1 was shown to suppress the JNK mediated apoptosis of selected cancer types and increase chemoresistance towards anthracylines (doxorubicin) and paclitaxel. Hence, Inhibition of MKP-1 is an attractive selective strategy for developing cancer therapeutic due to very scarce expression of MKP-1 in normal cells. Continuous research efforts have highlighted the potential of endophytic fungi inhabiting the medicinal plants as a potent repository for bioactive drugs of pharmaceutical importance. Currently, the PI has a repository of more than 80 endophytic fungi isolated from different medicinal plants of Northern Himalayan and desert region. Numerous reports indicated that diversified environmental conditions such as drought, high temperature and multiple extreme conditions are accountable for niche-specific diversity of the microbial population. Hence, the rational of this study lies in choosing medicinal plants inhabiting the Aravalli range of Rajasthan with anticancer potential. The present proposal is aimed at purifying the selective inhibitor(s) of MKP-1 from the endophytic fungi biomined from the medicinal plants inhabiting the Aravalli range of Rajasthan viz. C. gignatea, R. communis, M. pudica, M. oleifera, N. cadamba and L. macrophylla as prophylaxis of breast, colon and lung cancer. There exists very scarce work on screening microorganisms for anti-MKP-1 activity with endophytes as unexplored ecological niche. Bio-prospecting endophytic fungi in search of novel and effective MKP-1 inhibitor(s) is an amenable strategy with much favouring preliminary data. The proposed study shall pave the way to create a repository for harnessing novel potent anti-MKP-1 agents with identical functional and chemical properties as the parent medicinal plant. |