# Combination of Antidepressants and Chemotherapeutic Agents to Overcome P-Glycoprotein-Mediated Resistance in Cancer Patients: A Systematic Review

## TL;DR

This paper reviews how combining antidepressants with chemotherapy drugs may help overcome cancer drug resistance caused by a protein called P-glycoprotein.

## Contribution

The paper systematically reviews evidence for using antidepressants as chemosensitizers to enhance chemotherapy efficacy in P-glycoprotein-mediated drug resistance.

## Key findings

- Several antidepressants enhanced the cytotoxicity of chemotherapeutics in multidrug-resistant cancer models.
- Proposed mechanisms include P-glycoprotein downregulation and increased intracellular drug accumulation.
- The combination shows promise in preclinical models but requires clinical validation.

## Abstract

Background/Objectives: P-glycoprotein (P-gp, ABCB1/MDR1) is a key ATP-binding cassette transporter involved in multidrug resistance in cancer, limiting intracellular accumulation of various chemotherapeutic (CT) agents. Several antidepressants (ADs) have been shown to modulate P-gp function. This dual pharmacological profile raises the possibility of repurposing ADs as chemosensitizers to enhance anticancer drug efficacy. The objective of this review was to summarize the available evidence on the combined use of ADs and chemotherapeutics to overcome P-gp-mediated resistance. Methods: A systematic search was performed in PubMed, Scopus, and PsycInfo/PsycArticles databases using a comprehensive search string combining terms for P-gp, ADs, chemotherapy, and drug resistance. Inclusion criteria were preclinical or clinical studies investigating the effect of ADs in combination with chemotherapeutics on P-gp-mediated resistance in cancer models. Eleven relevant studies were identified and qualitatively analyzed. Results: Across diverse cancer models, including colon, breast, and multidrug-resistant cell lines, several ADs significantly enhanced the cytotoxicity of many chemotherapeutic agents. The proposed mechanisms involved downregulation of P-gp expression, inhibition of efflux activity, and increased intracellular drug accumulation. Conclusions: The combination of ADs with CT agents shows promising potential in overcoming P-gp-mediated multidrug resistance, enhancing antitumor efficacy in preclinical models. Further translational and clinical research is needed to validate these findings, optimize dosing strategies, and assess the risk–benefit profile in cancer patients, particularly those with comorbid depressive disorders.