Loperamide potentiates doxorubicin sensitivity in triple‐negative breast cancer cells by targeting MDR1 and JNK and suppressing mTOR and Bcl‐2: In vitro and molecular docking study

Abstract

Multidrug resistance (MDR) is the leading cause of treatment failure in triplenegative breast cancer (TNBC) patients treated with doxorubicin (DXR). We aimed to investigate the potential of the antidiarrheal drug Loperamide (LPR) in sensitizing TNBC cells to DXR and elucidate the underlying molecular mechanisms. Therefore, we examined the effects of DXR alone or in combination with LPR on MDA-MD-231 cells viability using MTT assay, cell cycle, and apoptosis by flow cytometry, and the expression of the MDR-related genes (MDR1 and JNK1) and cell cycle/survival genes (p21, mTOR, and Bcl-2) by quantitative reverse transcription polymerase chain reaction. Results showed that adding LPR to DXR potentiated its antiproliferation effect and reduced its IC50 by twofolds compared with DXR alone. The value of the combination index of LPR/DXR was <1 indicating a synergistic effect. Combined DXR/LPR treatment also caused G1 arrest and potentiated apoptosis more than DXR-single treatment. At the molecular levels, LPR/DXR treatment downregulated the mRNA of MDR1 (1.35-folds), JNK1 (2.5-folds), mTOR (6.6-folds), Bcl-2 (9.5folds); while upregulated p21 gene (8-folds) compared with DXR alone. Molecular docking analyses found LPR antagonizes MDR1 and JNK1 proteins, and hence supports the in vitro studies. In conclusion, the results confirmed the potential of LPR in sensitizing TNBCs to DXR by targeting MDR1 and JNK1 and suppressing Bcl-2 and mTOR genes, while upregulating the cell cycle inhibitor gene p21. Additionally, LPR could be repurposed to reduce the therapeutic doses of DXR as indicated by the dose reduction index (DRI) and subsequently decrease its side effects.

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation

“…One reason for this phenomenon may be P-gp overexpression. MDR1 overexpression is widely known as a resistance phenotype in different tumor subtypes [38,39]. Thus, our results indicated the importance of P-gp in canine PC resistance.…”

In Silico and In Vitro Studies for Benzimidazole Anthelmintics Repurposing as VEGFR-2 Antagonists: Novel Mebendazole-Loaded Mixed Micelles with Enhanced Dissolution and Anticancer Activity

“…The docking site was selected to be the ligand site, triangle matcher was chosen as the placement methodology, and London dG was selected as the scoring methodology. 91 The refinement methodology was selected as a rigid receptor and the scoring methodology was GBVI/WSA dG for the selection of the best poses. 11 , 86 The MDB file was generally docked automatically.…”

A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval

“…On the other hand, drug repurposing 26 , 28 , 50–56 is emerging as a good choice for COVID-19 treatment. 57–65 Drug repurposing strategy can be utilized via the use of already-approved effective drugs that show a promising avenue for their reuse for other indications, such as combating COVID-19.…”

“…Drug repurposing – so-called therapeutic switching – is the new application of already existing therapeutics to another disease indication. 25 , 26 The drug repurposing approach represents a rapid and low-cost drug discovery and development. 27 For example, recently repurposed drugs that were approved for treating coronary artery disease and erectile dysfunction were aspirin and sildenafil, respectively.…”