Cholesterol efflux pathways: role of caveolin and caveolae

530 0968 – 0004/00/$ – See front matter © 2000, Elsevier Science Ltd. All rights reserved. PII: S0968-0004(00)01668-6 SYSTEMIC CHEMOTHERAPY WITH cytotoxic drugs is a widely used treatment that improves long-term survival of cancer patients. Yet, it has been estimated that only ~10% of chemotherapy-treated patients are ultimately cured1. The main reason for the limited efficacy of chemotherapy is multidrug resistance (MDR), defined as cellular resistance to multiple, structurally and functionally divergent drugs. MDR can be intrinsic (i.e. primary tumors are refractory to drug treatment) or acquired (i.e. tumor cells acquire drug resistance during treatment and are refractory on relapse). In many cases, MDR is believed to be due to overexpression of a drug transporter that mediates an energydependent efflux of drugs (or drug conjugates) across the plasma membrane, thus reducing intracellular drug concentration. P-glycoprotein (P-gp), product of the human MDR1 gene, is a prototypic drug efflux ATPase that has been studied extensively2. Numerous studies have demonstrated that P-gp mediates unidirectional drug transport, that it exhibits a drug-dependent ATPase activity, as well as ATP-dependent drug binding, and that its expression reduces cell sensitivity to drugs1–3. Nevertheless, it is clear that in many cases drug resistance conferred by transfected P-gp alone is significantly less efficient than that of drug-selected MDR cell lines (Ref. 4 and citations therein). Hence, although P-gp and other drug transporters are necessary for drug efflux across the plasma membrane, they are not always sufficient for a full-fledged MDR phenotype in cancer cells. Acquisition of MDR by selection with increasing drug concentrations appears, therefore, to involve additional mechanisms that contribute to cellular drug resistance. Indeed, it is now recognized that MDR cells and tumors employ diverse mechanisms to prevent or circumvent the lethal effects of chemotherapeutic drugs (Fig. 1). Here we shall review recent results which suggest that cellular drug transport itself is more complex than previously thought and can involve the participation of caveolin-dependent cholesterol efflux pathways. It is postulated that these pathways can help deliver chemotherapeutic drugs from intracellular membranes to the plasma membrane against a steep concentration gradient. At the plasma membrane, drugs are extruded to the extracellular space by drug efflux pumps such as P-gp.