Evaluation of influence of Ap₄A analogues on Fhit-positive HEK293T cells; cytotoxicity and ability to induce apoptosis
2011
Krakowiak, Agnieszka | Pęcherzewska, Róża | Kaczmarek, Renata | Tomaszewska, Agnieszka | Nawrot, Barbara | Stec, Wojciech J.
Fragile histidine triad (Fhit) protein encoded by tumour suppressor FHIT gene is a proapoptotic protein with diadenosine polyphosphate (ApₙA, n=2–6) hydrolase activity. It has been hypothesised that formation of Fhit–substrate complex results in an apoptosis initiation signal while subsequent hydrolysis of ApₙA terminates this action. A series of ApₙA analogues have been identified in vitro as strong Fhit ligands [Varnum, J. M.; Baraniak, J.; Kaczmarek, R.; Stec, W. J.; Brenner, C. BMC Chem. Biol.2001, 1, 3]. We assumed that in Fhit-positive cells these compounds might preferentially bind to Fhit and inhibit its hydrolytic activity what would prolong the lifetime of apoptosis initiation signalling complex. Therefore, several Fhit inhibitors were tested for their cytotoxicity and ability to induce apoptosis in Fhit-positive HEK293T cells. These experiments have shown that Ap₄A analogue, containing a glycerol residue instead of the central pyrophosphate and two terminal phosphorothioates [APS-CH₂CH(OH)CH₂-PSA (1)], is the most cytotoxic among test compounds (IC₅₀=17.5±4.2μM) and triggers caspase-dependent cell apoptosis. The Fhit-negative HEK293T cells (in which Fhit was silenced by RNAi) were not sensitive to compound 1. These results indicate that the Ap₄A analogue 1 induces Fhit-dependent apoptosis and therefore, it can be considered as a drug candidate for anticancer therapy in Fhit-positive cancer cells and in Fhit-negative cancer cells, in which re-expression of Fhit was accomplished by gene therapy.
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