Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells

Breast Cancer Res Treat. 2000 Feb;59(3):231-44. doi: 10.1023/a:1006344200094.

Abstract

Paclitaxel (Taxol) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated >6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis* / drug effects
  • Breast Neoplasms / pathology*
  • Cyclosporins / pharmacology*
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Female
  • Fluorouracil / pharmacology
  • Humans
  • Paclitaxel / pharmacology*
  • Tumor Cells, Cultured / drug effects

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Cyclosporins
  • Doxorubicin
  • Paclitaxel
  • valspodar
  • Fluorouracil