Radiosensitization Effect of PARP Inhibitor Talazoparib Involves Decreasing Mitochondrial Membrane Potential and Induction of Cellular Senescence

TL;DR

This study shows that the PARP inhibitor talazoparib, when combined with radiation, increases cancer cell sensitivity by reducing mitochondrial function and inducing cell aging.

Contribution

The novel finding is that talazoparib's radiosensitization effect involves p21-dependent cellular senescence and mitochondrial disruption.

Findings

Talazoparib showed radiosensitization effects at the lowest concentration among tested PARP inhibitors.

Combining talazoparib with γ-irradiation induced cellular senescence and reduced mitochondrial membrane potential.

p21 gene knockdown attenuated both mitochondrial and senescence effects, indicating p21's role in radiosensitization.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) with radiation therapy can enhance the sensitivity of cancer cells by inhibiting DNA repair pathways. To determine the most suitable PARP inhibitor for radiosensitization in cancer cells, we compared various types of clinically used PARPis in lung cancer A549 cells. We found that most PARP inhibitors showed radiosensitization effects on A549 cells. ER10 values for talazoparib, olaparib rucaparib, ABT888 and niraparib were 1.5, 1.8, 2.8, 1.4, and 1.4, respectively. Talazoparib showed a radiosensitization effect at its lowest concentration. Talazoparib is a potent PARP inhibitor and has been used in clinical settings for several types of cancer as an anti-cancer agent. We thus focused on how talazoparib causes radiosensitization in lung cancer A549 cells. As a result of the combination of talazoparib and γ-irradiation, we observed an increased level of cellular senescence accompanied by a decrease in mitochondrial membrane potential. When the p21 gene was knocked down, both the decrease in mitochondrial membrane potential and senescence level were attenuated, suggesting that p21 is involved in senescence induction after γ-irradiation combined with talazoparib treatment. Taken together, we showed that PARP inhibitor talazoparib treatment in combination with γ-irradiation causes cellular senescence in lung cancer cells, involving p21 function.

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