Multifaceted impact of HIV inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy

Ketki Patil; Elizabeth Johnston; Joseph Novack; Garrett Wallace; Michelle Lin; S Balakrishna Pai

doi:10.1038/s41598-024-79789-y

Multifaceted impact of HIV inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy

Sci Rep. 2024 Dec 3;14(1):30103. doi: 10.1038/s41598-024-79789-y.

Authors

Ketki Patil^#¹, Elizabeth Johnston^#¹, Joseph Novack¹, Garrett Wallace¹, Michelle Lin¹, S Balakrishna Pai²

Affiliations

¹ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA.
² Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA. balakrishna.pai@bme.gatech.edu.

^# Contributed equally.

PMID: 39627279
DOI: 10.1038/s41598-024-79789-y

Abstract

Breast cancer is the most common cancer in women worldwide. Many breast cancers originate from the cells lining the milk duct and some become invasive. Breast cancer lacking estrogen, progesterone receptors (ER-, PR-) and epidermal growth factor receptor 2 (HER2-) amplification, termed "Triple negative" (TNBC) is reported to frequently affect Black women and younger women. TNBC is an invasive ductal carcinoma with limited treatment options. To this end, we opted to investigate drugs that could be repurposed because they offer advantages in bringing effective treatments faster to the clinic. We chose to study the effect of the drug, dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV because it could be detected in the breast milk of lactating women when treated for HIV and the drug could potentially target the cancer. Here we show the potent impact of dapivirine on MDA-MB-231 TNBC cells, while NNRTI like nevirapine showed marginal effects. When dapivirine was tested on other breast cell lines, MCF-7 and MCF 10A, the inhibition was at higher concentrations. Molecular studies with dapivirine in TNBC cells, revealed an increase in reactive oxygen species (ROS), apoptotic cells, and activation of caspases. Importantly, protein profiling and STRING analysis revealed deregulation of the key molecule, PCNA and impact on pivotal cell signaling circuits including extracellular matrix (ECM), angiogenesis, cell adhesion, and immunomodulation. Of note, is its potential effect on stem-like cells due to downregulation of the basic transcription factor 3 (BTF3) and proteasome activator complex subunit 3; the latter affecting their dependence on the proteasome pathway. Taken together, dapivirine exhibits the potential to be considered as a repurposed drug for TNBC as monotherapy/combination therapy. Notably, it could also potentially be a treatment for individuals with dual ailments, such as HIV and TNBC, if the clinical outcomes with dapivirine for TNBC become favorable.

Keywords: Apoptosis; Dapivirine; MDA-MB-231; Multicaspase; Proteomics; Triple negative breast cancer.

MeSH terms

Anti-HIV Agents / pharmacology
Anti-HIV Agents / therapeutic use
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Humans
MCF-7 Cells
Pyrimidines* / pharmacology
Pyrimidines* / therapeutic use
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism

Substances

Pyrimidines
Dapivirine
Anti-HIV Agents