Apoptotic induction on HeLa tumor cell line. A comparison of activity between pyrazolo[1,2-a]benzo[1,2,3,4]tetrazinone derivatives and their synthetic precursors.

Current advances on anticancer therapy point out the crucial role of apoptosis both in the regulation of cancer processes and in the consequent treatment response. Most anticancer strategies used in clinical oncology such as chemotherapy, ?-irradiation, suicide gene therapy or immunotherapy are correlated to the activation of apoptosis signal transduction pathways in cancer cells, involving an intrinsic or extrinsic pathway. For this purpose, the knowledge of biomolecular events and the design of new compounds, able to modulate the apoptotic process both as activators and inhibitors, provide new opportunities in the advance of new strategies for cancer therapy. Recently, a series of the pyrazolo[1,2-a] benzo [1,2,3,4] tetrazinone3 derivatives 2 were screened against a panel of 60 human tumor cell lines (NCI assays). All of these showed antiproliferative activity in the ?M range of concentration. In order to get some insight on the mechanism of action, we performed an apoptotic screening4 on HeLa tumor cell line on both the pyrazolo [1,2-a] benzo [1,2,3,4] tetrazinones 2 and the amine derivatives synthetic precursors 1. Preliminary results show a ten fold increase of tricycles biological activity compared to the amine derivatives. Probably the tetrazinone ring opening is not involved in the apoptotic mechanism.