Combination of talazoparib and olaparib enhanced the curcumin-mediated apoptosis in oral cancer cells by PARP-1 trapping.

PURPOSE

Inhibition of Poly (ADP-ribose) Polymerases (PARP) results in the blocking of DNA repair cascades that eventually leads to apoptosis and cancer cell death. PARP inhibitors (PARPi) exhibit their actions either by inhibiting PARP-induced PARylation and/or by trapping PARP at the DNA damage site. But, the mechanism of PARPi-mediated induction of cellular toxicity via PARP-trapping is largely unknown.

METHODS

The cellular toxicity of PARPi [Talazoparib (BMN) and/or Olaparib (Ola)] was investigated in oral cancer cells and the underlying mechanism was studied by using in vitro, in silico, and in vivo preclinical model systems.

RESULTS

The experimental data suggested that induction of DNA damage is imperative for the optimal effectiveness of PARPi. Curcumin (Cur) exhibited maximum DNA damaging capacity in comparison to Resveratrol and 5-Flurouracil. Combination of BMN + Ola induced cell death in Cur pre-treated cells at much lower concentrations than their individual treatments. BMN + Ola treatment deregulated the BER cascade, potentiated PARP-trapping, caused cell cycle arrest and apoptosis in Cur pre-treated cells in a much more effective manner than their individual treatments. In silico data indicated the involvement of different amino acid residues which might play important roles in enhancing the BMN + Ola-mediated PARP-trapping. Moreover, in vivo mice xenograft data also suggested the BMN + Ola-mediated enhancement of apoptotic potentiality of Cur.

CONCLUSION

Thus, induction of DNA damage was found to be essential for optimal functioning of PARPi and BMN + Ola combination treatment enhanced the apoptotic potentiality of Cur in cancer cells by enhancing the PARP-trapping activity via modulation of BER cascade.