CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

• Authors: Ashwini Makhale, Devathri Nanayakkara, Prahlad Raninga, Kum Kum Khanna, Murugan Kalimutho
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 11 (May 28 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34071360 (Publication Type: Journal Article)

Chemical References

• Benzothiazoles
• CX 5461
• Naphthyridines
• Quinuclidines
• RNA Polymerase I
• eprenetapopt

Topics

• Apoptosis (drug effects, genetics)
• Benzothiazoles (pharmacology)
• Cell Cycle (drug effects, genetics)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cell Survival (drug effects, genetics)
• DNA Damage
• DNA Replication (drug effects, genetics)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MCF-7 Cells
• Naphthyridines (pharmacology)
• Quinuclidines (pharmacology)
• RNA Polymerase I (antagonists & inhibitors, metabolism)
• Triple Negative Breast Neoplasms (genetics, pathology)