Resistance to chemotherapeutic drugs is a paramount problem in the treatment of cancer. Drug resistance may already exist before the initiation of therapy or may be acquired after successful initial therapy. Drug resistance, intrinsic or acquired, can be attributed to mutational (genetic) or nonmutational (epigenetic) processes in cancer cells. These processes frequently lead to the same biochemical mechanisms of drug resistance. Cancer cells become resistant to anticancer drugs by a variety of mechanisms, which include (1) decreased intracellular drug accumulation by decreased inward transport or by increased drug efflux; (2) increased drug inactivation or detoxification; (3) decreased conversion of drug to an active form; (4) altered quantity or activity of target proteins; (5) increased DNA repair capacity; (6) decreased apoptotic response; and (7) reversion to a more stem-like state by processes like an epithelial to mesenchymal transition (EMT).
Resistance to a broad spectrum of chemotherapeutic agents in cancer cell lines and human tumors has been called multidrug resistance (MDR). Treatment by one agent often results in the development of cross-resistance to different types of cytotoxic drugs. The most frequent mechanism is increased drug efflux, which is mediated by a large family of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and multidrug-resistance-associated proteins (MRP and BCRP).
P-gp, encoded by the ABCB1 gene, was the first identified mammalian multidrug transporter. Overexpression of P-gp causes cancer cells to become resistant to a great variety of structurally and functionally dissimilar antitumor drugs, including vinblastine, vincristine, doxorubicin, daunorubicin, etoposide, teniposide, and paclitaxel. Resistance to multiple drugs associated with reduced drug accumulation in human tumor cells can be conferred by other ABC transporters including the 190-kDa multidrug resistance protein MRP1, MRP2, MXR1 (also known as BCRP or ABCP), and ABCC10 (MRP7).
High levels of drug efflux transporters are characteristic of undifferentiated and stem cells, keeping them isolated from the environment. So any type of de-differentiation of cancer cells is typically accompanied by increased transporter expression and resistance to therapy. Stress pathways have similar effects, and are characteristically induced by drug treatment.
Among pathways known to affect transporter expression are the Ras/Raf/MEK/ERK cascade which couples signals from cell surface receptors to transcription factors in many cancer-related pathways. The phosphoinositide 3-kinase (PI3K) pathway, a critical signal transduction system linking oncogenes and multiple receptor classes to many essential cellular functions, is perhaps the most commonly activated signaling pathway in human cancer. Its downstream targets include several drug efflux transporters, either through gene expression or other mechanisms. Cyclo-oxygenase-2 (COX-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, has been shown to be overexpressed in a wide range of tumors and possesses proangiogenic and antiapoptotic properties. A close association between MDR and COX-2 expression has been reported in human colon cancer, and is involved in the development of the MDR phenotype in other studies.