Author(s): Ritu Jaiswal aff1 aff2 , Georges Emile Raymond Grau aff2
cancer; CD44; cellular communication; ezrin; microparticle; microRNA; multidrug resistance; multidrug-resistant-associated protein 1; p-glycoprotein; trait dominance
The clinical problem of drug resistance in the treatment of cancer
Although targeted therapies provide a rational and selective modality in cancer therapeutics, the development of drug resistance and the subsequent result of tumor unresponsiveness continue to plague clinical oncology. Drug resistance is seen when tumors that have been responding favorably to chemotherapeutic treatment suddenly reoccur or when the tumor fails to respond to initial treatment [1 ]. Numerous mechanisms contributing to drug resistance have been reported. These include reduced drug uptake, mutated and/or altered expression of drug targets, enzymatic inactivation of drugs, drug efflux mechanisms and alterations in apoptosis, senescence and repair mechanisms. In addition to resistance to a single drug, cancer cells often display a cross-resistance to a diverse range of unrelated drugs, resulting in a phenomenon known as multidrug resistance (MDR).
MDR in cancer
MDR is typically characterized by a cross-resistance to a wide range of pharmacologically unrelated drugs following the exposure of the cancer to a single anticancer agent [2 ]. MDR is mainly attributed to a reduced intracellular drug accumulation in cancer cells by virtue of increased drug efflux from within the cancer cell [ 3 ]. Consequently, sublethal intracellular drug concentrations are maintained and the cell survives cytotoxic drug exposure. Classical MDR is frequently attributed to the elevated expression of members of the ABC superfamily of membrane transporters. P-glycoprotein (ABCB1 /MDR1/P-gp) and ABCC1/ MRP1 comprise two of the most widely studied molecules that underpin mechanisms of active efflux implicated in cancer MDR.
P-gp & MRP1 & their role in conferring MDR
P-gp is a 170-kDa phosphoglycoprotein, encoded by the human ABCB1 gene, located on the long arm of chromosome 7, which utilizes energy released from ATP hydrolysis for drug efflux across cell membranes [ 4 ]. P-gp is a promiscuous drug transporter with a physiological role in binding and effluxing a wide array of structurally and functionally unrelated compounds, thereby protecting both cells and the organism as a whole from xenobiotics. This remarkable efflux capacity reduces the intracellular concentration of a wide range of chemotherapeutics, leading to MDR and anticancer treatment failure. Most, but not all P-gp substrates are hydrophobic organic compounds of large molecular weight ([greater than]400 g/mol) that are amphipathic, possess a planar ring system and carry a positive charge at physiological pH [5 ]. P-gp substrates therefore span various therapeutic drug classes including typical anticancer agents (anthracyclines, vinca alkoloids, and taxanes), HIV protease inhibitors, antipsychotics, natural products (colchicine and curcuminoids), linear and cyclic peptides, steroids, fluorescent dyes, [gamma]-emitting radiopharmaceuticals and many other miscellaneous agents [ 2,6 ].
The expression of the MDR1 or ABCB1 gene is often related to poor remission and survival rates across many malignancies, serving as a predictive indicator of anticancer treatment failure. P-gp overexpression is observed across many human cancers including hematopoietic cancers such as acute myeloid [7,8 ] and lymphoblastic leukaemia...