Selective Killing of Adriamycin-Resistant (G sub(2) Checkpoint-Deficient and MRP1-Expressing) Cancer Cells by Docetaxel

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 10; pp. 4401 - 4407
• Main Authors: Demidenko, Zoya N, Halicka, Dorota, Kunicki, Jan, McCubrey, James A, Darzynkiewicz, Zbigniew, Blagosklonny, Mikhail V
• Format: Journal Article
• Language: English
• Published: 15.05.2005
• ISSN: 0008-5472
• DOI: 10.1158/0008-5472.CAN-04-4428

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 G sub(2) 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 G sub(2), 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 G sub(2) arrest in the presence of Adriamycin. Also, in the presence of Adriamycin, HCT116-p21 super(-/-) cancer cells with a defective G sub(2) 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.