Drug Combinations: A New Strategy to Extend Drug Repurposing and Epithelial-Mesenchymal Transition in Breast and Colon Cancer Cells.

Abstract

Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major health problem. Drug repurposing coupled to drug combination strategies has been gaining interest among the scientific community. Recently, our group proposed novel drug combinations for breast and colon cancer using repurposed drugs from different classes (antimalarial and central nervous system (CNS)) and chemotherapeutic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), and found promising results. Here, we proposed a novel drug combination using different CNS drugs and doxorubicin (DOX), an antineoplastic used in breast cancer therapy, and studied their anticancer potential in MCF-7 breast cancer cells. Cells were treated with each drug alone and combined with increasing concentrations of DOX and cell viability was evaluated by MTT and SRB assays. Studies were also complemented with morphological evaluation. Assessment of drug interaction was performed using the CompuSyn and SynergyFinder software. We also compiled our previously studied drug pairs and selected the most promising ones for evaluation of the expression of EMT biomarkers (E-cadherin, P-cadherin, vimentin, and β-catenin) by immunohistochemistry (IHC) to assess if these drug combinations affect the expression of these proteins and eventually revert EMT. These results demonstrate that combination of DOX plus fluoxetine, benztropine, and thioridazine at their IC50 can improve the anticancer effect of DOX but to a lesser degree than when combined with PTX (previous results), resulting in most of the drug interactions being antagonist or additive. This suggests that the choice of the antineoplastic drug influences the success of the drug combination. Collectively, these results also allow us to conclude that antimalarial drugs as repurposed drugs have enhanced effects in MCF-7 breast cancer cells, while combination with CNS drugs seems to be more effective in HT-29 colon cancer cells. The IHC results demonstrate that combination treatments increase E-cadherin expression while reducing P-cadherin, vimentin, and β-catenin, suggesting that these treatments could induce EMT reversal. Taken together, these results could provide promising approaches to the design of novel drug combinations to treat breast and colon cancer patients.