2. Academic Validation
  3. CXCR4 inhibitor, AMD3100, down-regulates PARP1 expression and Synergizes with olaparib causing severe DNA damage in BRCA-proficient triple-negative breast cancer

CXCR4 inhibitor, AMD3100, down-regulates PARP1 expression and Synergizes with olaparib causing severe DNA damage in BRCA-proficient triple-negative breast cancer

  • Cancer Lett. 2022 Oct 6;215944. doi: 10.1016/j.canlet.2022.215944.
Xiao-Feng Xie 1,  Nan-Qiang Wu 2,  Jin-Feng Wu 3,  Guang-Lin Zhang 4,  Jin-Feng Guo 5,  Xue-Lian Chen 6,  Cai-Wen Du 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, N0. 113 Baohe Road, Shenzhen, 518116, PR China. Electronic address: xiezy1102@163.com.
  • 2 Department of Medical Oncology, Guangzhou First People's Hospital, No. 1, Panfu Road, Yuexiu District, Guangzhou, 510180, PR China. Electronic address: nanqiangwu@gmail.com.
  • 3 Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515031, PR China. Electronic address: 453928853@qq.com.
  • 4 Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515031, PR China. Electronic address: 576083004@qq.com.
  • 5 Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, N0. 113 Baohe Road, Shenzhen, 518116, PR China. Electronic address: gjf1229466422@163.com.
  • 6 Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, N0. 113 Baohe Road, Shenzhen, 518116, PR China. Electronic address: linda208@aliyun.com.
  • 7 Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, N0. 113 Baohe Road, Shenzhen, 518116, PR China; Shenzhen University, Hlth Sci Ctr, Sch Pharmaceut Sci, Shenzhen, No, 3688, Nanhai Road, Nanshan District, 518060, Shenzhen, PR China. Electronic address: dusumc@aliyun.com.
PMID: 36209974 DOI: 10.1016/j.canlet.2022.215944
Abstract

Poly ADP-ribose polymerase inhibitor (PARPi) treatment is effective in triple-negative breast Cancer (TNBC) with BRCA mutation. However, its efficacy in BRCA-proficient TNBC remains unexplored. It is, therefore, an exciting proposition to broaden the indication of PARPi for BRCA-proficient TNBC patients. Chemokine Receptor (CXCR4) is a transmembrane G protein-coupled receptor, which is involved in cell migration, proliferation, Apoptosis, and damage repair, and it initiates many signalling pathways. Although administration of CXCR4 Inhibitor alone is not ideal as a target drug, it can play a strong synergistic role in combination with other drugs. We explored the effect of CXCR4 and PARP1 on tumour cell proliferation, migration, metastasis, and Apoptosis in vitro and in vivo and found that a CXCR4 Inhibitor, AMD3100, enhanced the anti-tumour effect of PARP1 Inhibitor, olaparib, on BRCA-proficient TNBC. When CXCR4 was inhibited and silenced, DNA damage repair and DNA replication fork activity were suppressed by up-regulating caspase-3-mediated increase in PARP1 cleavage; in combination with the inhibition of PARP1, AMD3100 resulted in the accumulation of fatal DNA damage and induction of Apoptosis. This combination regimen can be effective against BRCA-proficient TNBC.

Keywords

Apoptosis; Caspase-3; DNA damage Marker γH2AX; Poly ADP-Ribose polymerase inhibitor (PARPi); Sensibilization.

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