Radiosensitization Effect of PARP Inhibitor Talazoparib Involves Decreasing Mitochondrial Membrane Potential and
Barkha Saraswat1, Ankitha Vadi Velu1, Zhongming Gao1
1Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan.
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.
Insights
Poly (ADP-ribose) polymerase inhibitors enhance cancer cell sensitivity to radiation therapy. Talazoparib combined with radiation induces senescence in lung cancer cells, involving p21.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPis) target DNA repair pathways.
- PARPis combined with radiation therapy show potential for cancer treatment.
Purpose of the Study:
- To compare the radiosensitization effects of various PARPis in lung cancer cells.
- To investigate the mechanism of talazoparib-induced radiosensitization.
Main Methods:
- Comparison of clinically used PARPis in A549 lung cancer cells.
- Assessment of radiosensitization using ER10 values.
- Analysis of cellular senescence, mitochondrial membrane potential, and p21 gene expression.
Main Results:
- Most tested PARPis demonstrated radiosensitization effects.
- Talazoparib exhibited radiosensitization at the lowest concentration.
- Combination of talazoparib and gamma-irradiation increased cellular senescence and decreased mitochondrial membrane potential, dependent on p21.
Conclusions:
- Talazoparib is a potent PARP inhibitor with significant radiosensitization effects.
- Talazoparib combined with radiation induces p21-dependent cellular senescence in lung cancer cells.
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