Use of bioaffinity chromatography in the prospecting of anticancer substances in marine actinomycetes: XIAP and STMN1 as pharmacological targets

Abstract

The marine environment is an exceptional warehouse for new bioactive natural products with unique structural and chemical characteristics, including those with anticancer properties. A major obstacle in pharmacology is the elucidation of the pharmacological target. Using a directed target approach at targets that have relevance for cancer is interesting in order to reduce costs and maximize time, since by doing this approach there is no problem of elucidation of the pharmacological target. Two interesting targets for anticancer therapy, because of their overexpression in cancer cells something that does not occur in normal cells, are XIAP and STMN1. These proteins interact thanks to a crosstalk of their pathways that are modulated by another protein called SIVA1. XIAP is an Apoptosis Inhibitor Protein (IAPs). This family of proteins is involved in the regulation of a number of cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. Overexpression of these proteins is common in tumors, whereas in normal tissues they are almost or totally absent. The ability to prevent cell death is a characteristic of tumor cells and one of the mechanisms of resistance to current anticancer treatment. Therefore, reactivation of cell death is a promising strategy for treatment innovation. XIAP prevents apoptosis by direct binding and inhibition of three caspases (caspase-9 initiator and two effectors, caspase-3 and 7). Another interesting target that is also overexpressed in tumor cells is STMN1, a phosphoprotein that regulates the dynamics of microtubules and accelerates cell cycle proliferation and progression. Overexpression of STMN1 is associated with a variety of cancers in humans, such as breast cancer, prostate, colon carcinoma and malignant hematopoietic cells. It is important to note that specific inhibition of STMN1 using shRNA reduces the proliferation and clonogenicity of leukemic cells. Bioaffinity chromatography is a novel technique and can be used to find biological affinity between proteins of interest and extracts which exhibit cytotoxicity, since it implants the biological affinity as the matrix for the isolation of the compound. In this way, this project aims to find substrates that contain bioactive compounds that interact with two important pathways in the maintenance of cancer from an innovative technique, validating at the end this biological activity in cellular models. (AU)