Exploring the multi-drug resistance (MDR) inhibition property of Sildenafil: phosphodiesterase 5 as a therapeutic target and a potential player in reversing MDR for a successful breast cancer treatment

Abstract

In recent years, there has been an increase in both the incidence and mortality of breast cancer. Globally, breast cancer is ranked as the main root of cancer-related death in women. Multidrug resistance (MDR) is identified as a primary cause of treatment failure in anticancer chemotherapy. This makes multidrug resistance an interesting therapeutic target in breast cancer. Therefore, elucidation of the molecular mechanisms involved in chemoresistance is essential. Phosphodiesterase 5 (PDE5) cross-talks with nitric oxide/cyclic guanosine monophosphate (NO/cGMP), Wnt/β-catenin, and PI3K/Akt signaling pathways to upregulate the expression of ABC transporters and increase cGMP efflux. This enhances multidrug resistance and impacts cellular processes such as proliferation, apoptosis, and angiogenesis. Thus, further research on the identification of possible factors in the reversal of MDR in breast cancer is necessary. Sildenafil is a selective phosphodiesterase type 5 inhibitor that is commonly utilized as first-line therapy in treating erectile dysfunction. Its safety profile and tolerability have encouraged researchers to develop an interest in further investigations into its beneficial uses, especially its chemo-preventive activity in managing breast cancer. In this review, we critically examined the central role played by PDE5 in activating several pathways involved in MDR in breast cancer. Given that sildenafil is a selective PDE5 inhibitor, we provide insight into its modulatory effects and interactions with signaling pathways targeted by PDE5 to overcome MDR in breast cancer.