Reversal effects of local anesthetics on P-glycoprotein-mediated cancer multidrug resistance.

Abstract

The existence of multidrug resistance (MDR) is the main reason for failure in cancer chemotherapy. The main mechanism of MDR is the overexpression of P-glycoprotein (P-gp). P-gp, a 170 kDa transmembrane phosphorylated glycoprotein encoded by ABCB1 belonging to a member of the ATP-binding cassette (ABC) super-family of the membrane transporters, is also known as the MDR protein. Local anesthetics (LAs) are a major contributor to medical practice. As a cornerstone of analgesia, LAs provides myriad benefits. Recent studies have shown that the LAs can interfere with receptors other than the traditional sodium channel. LA can suppress the proliferation of several cancer cells. The inhibition of P-gp could reverse MDR. Interestingly, the LAs, such as lidocaine, can repress ABCB1 (P-gp) expression and reverse MDR. Also, LAs can modulate the tumor necrosis factor/AKT pathway, the tumor necrosis factor/Src pathway, epidermal growth factor receptor, the Wnt pathway, and the RASSF1A/MDM2/p53 pathway to interfere with P-gp function. This means that LAs could be potentially useful in reversing cancer MDR. The aim of this review is to report the nonanesthetic functions of LAs, with a special focus on their anti-MDR effects and their potential beneficial implications in cancer chemotherapy.