Combination Drug Discovery in the Treatment of Multidrug-resistant Preclinical Models of Breast Cancer

Abstract

Therapeutic resistance is the culprit behind most cancer-related relapse and death, accounting for over 90% chemotherapeutic intervention failures. To combat the genetic and phenotypical abnormalities associated with resistant cancer cells, combination therapy takes the centre stage. Here, we identified a commercially available molecule, which we renamed as “BC-2021,” and its ability to sensitize multidrug-resistant triple-negative and hormone receptor-positive breast cancer cells to the challenge of Taxol in short-term and longer-term in vitro studies. 1μM of BC-2021 alone did not pose acute cytotoxicity towards non-cancerous cells, whereas 1μM of BC-2021 in combination with 585nM of PLX induced apoptosis among resistant breast cancer cells. It is noteworthy that the observed cell death was not accompanied by elevated total or mitochondrial reactive oxygen species, nitric oxide levels, and microtubule stabilization. Instead, the combination regimen predominantly induced extensive G2/M phase cell cycle arrest, resulting in BC-2021 dose-dependent nuclear fragmentation.