Resistance To Cisplatin Results From Multiple Mechanisms In Cancer Cells

We have studied the development of resistance to cisplatin in cultured KB-3-1 human cervical adenocarcinoma (HeLa) cells and BEL-7404 human hepatoma cells. In a single-step selection, it is possible to develop a pleiotropic phenotype consisting of the following: (a) cross-resistance to other platinum compounds, arsenite, cadmium, methotrexate and nucleoside analogs; (b) corresponding reduced accumulation of these agents; (c) reduced receptor-mediated and fluid phase mediated endocytosis; (d) altered cytoskeleton, including disruption of actin microfilaments, filament structures, and microtubules; (e) a defect in membrane protein trafficking consisting of relocalization to intracellular vesicles of several transmembrane proteins Such as the ABBC1 transporter (MRP1, GS-X pump), glucose transporter (GluT1), and folate binding protein (FBP); and (f)altered mitochondrial morphology and function. We hypothesize that this pleiotropic phenotype reflects a basic cellular defense mechanism against cytotoxic materials that are not hydrophobic enough to enter the cell by simple diffusion, but have multiple other mechanisms of cell entry including piggybacking on existing receptors and endocytosis, and speculate that a relatively simple cellular switch can actuate this pleiotropic response.