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Research ArticleExperimental Studies

A P-glycoprotein- and MRP1-independent Doxorubicin-resistant Variant of the MCF-7 Breast Cancer Cell Line with Defects in Caspase-6, -7, -8, -9 and -10 Activation Pathways

SOO-JUNG PARK, CHING-HAUNG WU and AHMAD R. SAFA
Anticancer Research January 2004, 24 (1) 123-132;
SOO-JUNG PARK
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CHING-HAUNG WU
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AHMAD R. SAFA
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Abstract

Background: Several mechanisms are known to cause resistance to chemotherapy in cancer cells, but the mechanisms of drug resistance due to a lack of apoptosis are not well elucidated. Materials and Methods: To understand the mechanisms of resistance to apoptosis induced by doxorubicin (DOX), we developed a DOX-resistant variant of MCF-7 referred to as MCF-7/Adr-20, measured growth inhibition by methylene blue cell survival assay, quantitated apoptosis by annexin V binding assay and detected activation of caspases-6, -7, -8, -9 and -10 in these cells. Results: The resistant cells expressed 20-fold resistance to apoptosis induced by DOX compared to MCF-7 cells. MCF-7/Adr-20 cells did not express MDR1 mRNA or its product P-lycoprotein and they did not overexpress MRP-1. Treating MCF-7 cells with 0.01, 0.1 and 1 μM DOX for 72 h induced 8, 14 and 28% apoptosis, respectively. However, only 1 μM DOX was able to trigger about 8% apoptosis in MCF-7/Adr- 20 cells. Moreover, apoptosis triggered by 0.01 and 0.1 μM DOX in MCF-7 cells was mainly caspase-dependent, but at 1 μM about 70% of apoptosis was caspase-dependent. Western blot analysis revealed that caspase-7 was activated at 0.1 and 1 μM DOX treatment and caspases-6, -8, -9 and 10 were only activated at 1 μM DOX treatment in MCF-7 cells, but none of the caspases checked were activated in MCF-7/Adr-20 cells. Moreover, DOX at 0.01 and 0.1 μM induced p53 and p21WAF1/CIP-1 to the same extent in both MCF-7 and MCF-7/Adr-20 cells. Therefore, while DOX triggers growth arrest and induces p53 and p21WAF-1/CIP-1 in these cells, defects in activation of the initiator and executioner caspases play a major role in resistance to apoptosis triggered by DOX.

  • Received September 29, 2003.
  • Accepted October 17, 2003.
  • Copyright© 2004 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 24 (1)
Anticancer Research
Vol. 24, Issue 1
January-February 2004
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A P-glycoprotein- and MRP1-independent Doxorubicin-resistant Variant of the MCF-7 Breast Cancer Cell Line with Defects in Caspase-6, -7, -8, -9 and -10 Activation Pathways
SOO-JUNG PARK, CHING-HAUNG WU, AHMAD R. SAFA
Anticancer Research Jan 2004, 24 (1) 123-132;

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A P-glycoprotein- and MRP1-independent Doxorubicin-resistant Variant of the MCF-7 Breast Cancer Cell Line with Defects in Caspase-6, -7, -8, -9 and -10 Activation Pathways
SOO-JUNG PARK, CHING-HAUNG WU, AHMAD R. SAFA
Anticancer Research Jan 2004, 24 (1) 123-132;
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