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CXCR4 inhibitor, AMD3100, down-regulates PARP1 expression and Synergizes with olaparib causing severe DNA damage in

Xiao-Feng Xie1, Nan-Qiang Wu2, Jin-Feng Wu3

  • 1Department 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.

Cancer Letters
|October 9, 2022
PubMed

Insights

Poly ADP-ribose polymerase inhibitor (PARPi) and chemokine receptor (CXCR4) inhibitors show promise for BRCA-proficient triple-negative breast cancer (TNBC). Combining olaparib with AMD3100 enhances anti-tumor effects and induces apoptosis in TNBC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Poly ADP-ribose polymerase inhibitors (PARPi) are effective in BRCA-mutated triple-negative breast cancer (TNBC).
  • The efficacy of PARPi in BRCA-proficient TNBC is largely unexplored.
  • Chemokine receptor CXCR4 plays a role in tumor progression and can synergize with other therapies.

Purpose of the Study:

  • To investigate the combined effect of CXCR4 and PARP1 inhibition in BRCA-proficient TNBC.
  • To determine if CXCR4 inhibition enhances the efficacy of PARP1 inhibitors like olaparib.
  • To explore the mechanisms underlying the synergistic anti-tumor activity.

Main Methods:

  • In vitro and in vivo studies were conducted.
  • The effects of CXCR4 inhibitor AMD3100 and PARP1 inhibitor olaparib were evaluated.
  • Mechanisms involving DNA damage repair, replication fork activity, and apoptosis were assessed.

Main Results:

  • AMD3100, a CXCR4 inhibitor, significantly enhanced the anti-tumor efficacy of olaparib in BRCA-proficient TNBC models.
  • Inhibition and silencing of CXCR4 suppressed DNA damage repair and replication fork activity.
  • The combination therapy led to increased PARP1 cleavage, fatal DNA damage, and apoptosis induction.

Conclusions:

  • Combining CXCR4 inhibition with PARP1 inhibition is a promising strategy for treating BRCA-proficient TNBC.
  • This combination regimen effectively targets tumor cell proliferation, migration, and induces apoptosis.
  • The findings suggest a potential new therapeutic option for TNBC patients with proficient BRCA status.
Keywords:
ApoptosisCaspase-3DNA damage Marker γH2AXPoly ADP-Ribose polymerase inhibitor (PARPi)Sensibilization

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