Selective Killing of Adriamycin-Resistant (G2 Checkpoint-Deficient and MRP1-Expressing) Cancer Cells by Docetaxel

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Abstract
Chemotherapy of cancer is limited by toxicity to normal cells. Drug resistance further limits the therapy. Here, we investigated selective killing of drug-resistant cancer cells by antagonistic drug combinations, which can spare (because of drug antagonism) normal cells. We used paired cell lines that are resistant to Adriamycin due to either expression of MRP1 or lack of G2 checkpoints. The goal was to selectively kill Adriamycin-resistant cancer cells with Docetaxel (Taxotere), while protecting parental (Adriamycin-sensitive) cells, using cytostatic concentrations of Adriamycin. Taxotere kills cells in mitosis. Therefore, by arresting parental cells in G2, 20 to 40 ng/mL of Adriamycin prevented cell death caused by Taxotere. Also, Adriamycin prevented the effects of Taxotere in normal human lymphocytes. In contrast, Taxotere selectively killed MRP1-expressing leukemia cells, which did not undergo G2 arrest in the presence of Adriamycin. Also, in the presence of Adriamycin, HCT116-p21−/− cancer cells with a defective G2 checkpoint entered mitosis and were selectively killed by Taxotere. Finally, 20 ng/mL of Adriamycin protected normal FDC-P1 hematopoietic cells from Taxotere. Whereas parental cells were protected by Adriamycin, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD90598 potentiated the cytotoxic effect of Taxotere selectively in Raf-1–transformed FDC-P1 leukemia cells. We propose a therapeutic strategy to prevent normal cells from entering mitosis while increasing apoptosis selectively in mitotic cancer cells.

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