36P - Abacavir potentiates the efficacy of doxorubicin in breast cancer cells via KDM5B Inhibition

Background

KDM5B, a transcriptional repressor, is significantly upregulated in various cancers. Our study aimed to assess the prognostic importance of KDM5B in breast cancer (BC) and to identify small molecules targeting it, using bioinformatics, clinical, in silico, and in vitro tools. Doxorubicin (DOX) is widely used in BC chemotherapy; however, cardiotoxicity and drug resistance remain significant issues. We demonstrate that repurposing the antiviral drug abacavir (ABC) for epigenetic targeting of KDM5B, offers a promising strategy to enhance the efficacy of DOX.

Methods

We analyzed the oncogenic implications of KDM5B using TCGA, GEPIA, UALCAN, CancerSEA, and cBioportal databases. KDM5B mRNA expression was also analyzed in 20 paired BC and adjacent normal tissues using qRT-PCR. ABC and its metabolites carbovir monophosphate (CBM) and carbovir triphosphate (CBT) were assessed for their affinity towards KDM5B through molecular docking. Additionally, we investigated the impact of ABC sensitization on DOX efficacy on BC cells (MDA-MB-231 and MCF-7) through MTT assay, colony formation assay, apoptosis study, and cell cycle analysis.

Results

Data from various portals revealed that KDM5B gene expression was higher in BC tissues compared to normal. In addition, KDM5B expression was significantly associated with BC subtypes, stages, and p53 mutation. Consistent with global data, KDM5B gene was upregulated in 11 out of 20 BC tissues. Molecular docking analyses identified key interactions of ABC, CBM, and CBT toward KDM5B. In vitro investigations demonstrated reduced KDM5B expression in ABC-treated BC cells as well as enhanced sensitization of BC cells towards DOX. Furthermore, ABC induced late apoptosis and S phase arrest, whereas ABC+DOX showed S/G2 phase arrest, late apoptosis, and cell death. Additionally, a significant reduction in cell colonies was observed with ABC+DOX in comparison to DOX alone.

Conclusions

Our findings highlight the repurposing potential of ABC, a well-known antiviral agent, to target the KDM5B oncogene in BC. This strategy may enhance the efficacy of DOX and could potentially help in reducing its dose, side effects, and drug resistance, thereby offering a promising approach for personalized BC treatment.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Department of Science and Technology (DST) INSPIRE Fellowship and Manipal Academy of Higher Education contingency fund.

Disclosure

All authors have declared no conflicts of interest.