Drug Resistance Mechanisms in Cancer Cells

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A major obstacle in the successful treatment of cancer is the development of resistance mechanisms to drug treatment. Various cellular changes that have been implicated in the development of drug resistance in cancer cells include: the increased expressions of P-glycoprotein (a multidrug transport protein) and multidrug resistance-associated protein (MRP-1); increased levels of the cellular detoxification protein, glutathione; and changes in the expression of apoptosis associated proteins such as Bcl-2, FasL and p53, which generally results in promoting cell survival [1,2,3,4].

P-glycoprotein expression is the mechanism mostly associated with classical multidrug resistance (MDR), as this protein is responsible for the active transport of various drugs out of the cell, thereby decreasing drug accumulation [1,3]. Not much is known in regards to how MRP-1 confers multidrug resistance, a notable exception is that its expression has been associated with a decrease in drug accumulation similar to P-glycoprotein [1]. Glutathione is an important cellular antioxidant and detoxification protein, and its increased levels have been observed to inactivate various chemotherapeutic drugs [2]. Bcl-2 is a known inhibitor of apoptosis and its cellular overexpression has been observed to increase resistance to drugs whose mechanism of action involve apoptotic initiation [2]. FasL (Fas ligand), upon binding, induces apoptosis in cells expressing Fas receptors. As such, FasL interaction is a characteristic mechanism by which cytotoxic T lymphocytes and particular chemotherapeutic agents induce apoptosis [3]. Decreased expressions of FasL mediated apoptosis have been observed to be associated with cell sublines brought up to confer resistance to these chemotherapeutic agents [3]. P53 also induces apoptosis and mutations and alterations in the gene encoding p53 are the most frequent abnormalities detected in malignancies and has been observed to contribute to...
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