2-Pyridineformamide N(4)-ring incorporated thiosemicarbazones inhibit MCF-7 cells by inhibiting JNK pathway

In an effort to develop a more potent anticancer therapeutic agent, a series of 2-pyridineformamide thiosemicarbazones (R = H, 4-CH₃, 5-F, 6-CH₃ and ) have been synthesized and evaluated for their anti-cancer activities against the cancer cells MCF-7 (breast cancer cell line), A-431 and A375 (epidermoid carcinoma cell line), and HeLa (cervical cancer cell line) using MTT assay. All these 2-pyridineformamide thiosemicarbazones exhibited anti-proliferative activities towards these cell lines. 5FAmPyrr possess most profound effects against MCF-7 cells with IC₅₀ of 0.9 µM. In flow cytometry using Propidium Iodide, 5FAmPyrr was found to induce cell death significantly in a dose dependent manner (100 nM-3 µM) and inhibited colony formation of MCF-7 cells. This compound induced pro-apoptotic protein Bax and inhibited anti apoptotic protein Bcl-2 as well as both c-Jun and Jun N-terminal kinase (abbreviated as JNK) in concentration dependent manner. Further pro-caspase 3 and PARP were inhibited by 5FAmPyrr at concentration of 3 µM. The results suggest that 5FAmPyrr exhibit anticancer potency and induced cell death by inhibiting MAPK signaling and inducing intrinsic apoptotic pathway. All these indicate that 2-pyridineformamide thiosemicarbazones could be developed as future therapeutics agents to treat cancer.