RND family efflux pumps: from antibioresistance to chemotherapy resistance

Abstract

Resistance to chemotherapy can be studied comparatively to the study of resistance in microorganisms. For over 40 years, understanding mechanisms that confer MDR has been a major goal of cancer biologists. Most of the studies toward MDR in cancer cells were about ABC transporters. Unfortunately, inhibition of these transporters often resulted in over toxicity due to the important role of these ABC transporters in healthy cells. The discovery of other targets for MDR of resistant cancer cells is of significant interest. Among the protein superfamily identified as being responsible for multidrug resistance are RND. Its members are widespread in bacterial organisms, but also in Archaea and Eukaryotes. Among the common features of multidrug resistance in RND is the ability of these transmembrane proteins to efflux a broad spectrum of substrates and drugs using the proton motive force. Ptch1, member of the RND family, is overexpressed in many aggressive and metastatic cancers. Like other members of the RND family such as NPC1, it is able to transport cholesterol. It was later shown to transport chemotherapeutic drugs, and its inhibition in resistant cancer cell lines resulted in increasing chemotherapeutic treatment efficacy. However, the drug efflux mechanism of Ptch1 is still unknown. In this review, we will discuss the possibility of a drug efflux mechanism common to the different proteins from the RND family.

Inhibition of the drug efflux activity of Ptch1 as a promising strategy to overcome chemotherapy resistance in cancer cells

“…Ptch1 has a sterol sensing domain (SSD) and a large nonstructured intracellular domain like the Niemann Pick C1 protein (NPC1). It belongs to the Resistance-Nodulation-Division (RND) superfamily which also includes efflux pumps mostly of bacterial origin [37]. RND transporters can extrude a wide variety of substrates such as sterols, lipids, bile salts, fatty acids, and metal ions, as well as lipophilic drugs, and are involved in drug resistance [38].…”