An in vitro and in vivo study to evaluate anticancer activity of glutamine conjugated organotin derivatives in colon cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy worldwide. Metallodrugs, particularly cisplatin and its analogs, are effective chemotherapeutic agents for cancer treatment. However, their significant off-target toxicity and drug resistance encouraged the development of non-platinum candidates such as organotin(IV) Schiff base compounds. These compounds have been reported to exhibit notable anticancer effects in various in vitro studies owing to the structural framework that determines their biological activity. Targeted therapy is an attractive approach to enhance the therapeutic effect and successfully prolong overall survival for CRC patients. To sustain aberrant proliferation, cancer cells undergo metabolic reprogramming that causes glutamine addiction to maintain cellular biosynthesis and cell growth. The present study is designed to synthesize organotin(IV) Schiff base compounds conjugated with glutamine that will allow their preferential delivery to cancer cells and reduce off-target toxicity. These compounds were investigated for pharmacokinetics and drug-likeness properties using in silico ADME analysis, binding affinities with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA), and their cytotoxicity against human colon carcinoma and adenoma-derived cell lines. The results revealed that these compounds displayed excellent pharmacokinetic profiles, strong binding affinities and distinct binding modes with DNA and protein, and strong cytotoxic activity against colon cancer cells. Further, mechanistic studies confirmed that these compounds induced G2/M phase cell cycle arrest and apoptotic cell death in these cell lines. In addition, the chemotherapeutic potential of these compounds was determined in the DMH/DSS-induced experimental colon carcinogenesis model system. These compounds significantly inhibited cell proliferation and induced apoptosis-mediated cell death.