Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer Cells by Inhibiting DNA Damage Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

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Abstract 1137: PRMT5 inhibition regulates alternative splicing and DNA damage repair pathways in SF3B1 R625G expressing uveal melanoma cells

10.1158/1538-7445.am2021-1137 ◽

2021 ◽

Author(s):

Koichi Ito ◽

Venkat Thodima ◽

Jack Carter ◽

Neha Bhagwat ◽

Monisha Sivakumar ◽

...

Keyword(s):

Dna Damage ◽

Alternative Splicing ◽

Uveal Melanoma ◽

Dna Damage Repair ◽

Melanoma Cells ◽

Damage Repair ◽

Repair Pathways

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Enzalutamide Potentiates Radiation Response via Impairment of DNA Damage Repair Process in Prostate Cancer Cells

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2017.06.1165 ◽

2017 ◽

Vol 99 (2) ◽

pp. E235

Author(s):

M. Ghashghaei ◽

T.M. Muanza ◽

M. Paliouras ◽

T.M. Niazi

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Repair ◽

Repair Process ◽

Radiation Response ◽

Prostate Cancer Cells ◽

Damage Repair

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APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738502 ◽

2021 ◽

Vol 9 ◽

Author(s):

Md Akram Hossain ◽

Yunfeng Lin ◽

Garrett Driscoll ◽

Jia Li ◽

Anne McMahon ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Response ◽

Human Pancreatic Cancer ◽

Genome Integrity ◽

Pancreatic Cancer Cells ◽

Damage Response ◽

Egg Extracts

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

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