Big Kids: Multidrug Resistance
Multidrug resistance (MDR), a major cause of cancer treatment failure, is a phenomenon whereby cancer cells develop broad resistance to a wide variety of chemotherapeutic drugs. MDR has been associated with overexpression of P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP), two transmembrane transporter molecules which act as pumps to remove toxic drugs from tumor cells. Evidence for an additional mechanism of MDR has recently come from in vitro and clinical studies on an MDR-associated protein originally termed Lung Resistance-related Protein (LRP). Rik Scheper and his colleagues at Free University in the Netherlands, isolated and sequenced a cDNA coding for the LRP gene and found it to be the human major vault protein. LRP/MVP is overexpressed in a wide variety of Pgp negative MDR cancer cell lines including some that are MRP negative. In a study on human cancer lines not selected for drug resistance, LRP/MVP showed the greatest individual value as a marker of in vitro resistance to a broad variety of drugs and LRP/MVP expression in human tumors supports the value of this protein as a marker of clinical resistance to chemotherapy. Cytotoxic drugs are known to accumulate in the nucleus. There are numerous mechanism that the cell could utilize to rid itself of cytotoxic drugs i.e., by modifying the drugs, by upregulation of plasma membrane pumps or by lowering the nuclear-cytoplasmic ratio by increasing drug export out of the nucleus. All of these mechanisms have been identified in various MDR cell types.
This new and unexpected role for vaults lends further support to the notion that vaults are involved in nucleo-cytoplasmic transport and that cytotoxic drugs may be one of their transport substrates.
A study of several non-Pgp multidrug resistant cell lines with increased MVP levels has demonstrated that both the vault RNA and the major vault protein are coordinately regulated (see figure at left). This suggests that the entire vault particle is upregulated in MDR. Furthermore, there appears to be a threshold level of vaults required to impart MDR.
