Sphingolipid abnormalities in cancer multidrug resistance: Chicken or egg?

The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer. Here we postulate that increased sphingomyelin content, developing early in some cancers, recruits and functionalizes plasma membrane ABCB1 conferring a state of partial MDR, which is completed by glycosphingolipid disturbance and the appearance of intracellular vesicular ABCB1. In this review, the independent and interdependent roles of sphingolipid alterations and ABCB1 upregulation during the transformation process and resultant conferment of partial and complete MDR phenotypes are discussed.