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Pleiotropic drug resistance and survival advantage in leukemic cells with diminished apoptotic response

O S Frankfurt1, D Seckinger, E V Sugarbaker

  • 1Oncology Laboratory, Cedars Medical Center, Miami, Fl 33136.

International Journal of Cancer
|October 15, 1994
PubMed

Insights

Acquired pleiotropic drug resistance in R9 cells stems from a reduced apoptotic response, independent of bcl-2. This diminished apoptosis mechanism, while enhancing survival, may drive neoplastic progression.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Pharmacology

Background:

  • Acquired pleiotropic drug resistance is a significant challenge in cancer therapy.
  • MOLT-4 cells exposed to adriamycin developed a resistant cell line (R9).
  • Understanding the mechanisms of drug resistance is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the mechanism of acquired pleiotropic drug resistance in the R9 cell line.
  • To determine if diminished apoptotic response contributes to this resistance.
  • To explore the role of bcl-2 protein and CD4 expression in drug resistance.

Main Methods:

  • Continuous exposure of MOLT-4 cells to adriamycin to generate R9 cells.
  • Assessing apoptosis induction by various agents (drugs, medium depletion, serum deprivation).
  • Quantifying DNA degradation in apoptotic cells and measuring cell division/DNA synthesis inhibition.
  • Analyzing bcl-2 protein levels and CD4 surface antigen expression.

Main Results:

  • R9 cells exhibited cross-resistance to multiple drugs, linked to a decreased apoptotic response.
  • Apoptosis induction and DNA degradation were reduced in R9 cells compared to sensitive cells.
  • Drug-induced inhibition of cell division and DNA synthesis was similar in both cell lines.
  • Resistance was bcl-2-independent, but CD4 expression was lost in R9 cells.
  • Alkylating agents showed similar cytotoxicity and only slightly reduced apoptosis in R9 cells.

Conclusions:

  • Acquired pleiotropic drug resistance in R9 cells is mediated by a bcl-2-independent, diminished apoptotic response.
  • This resistance mechanism enhances cell survival under adverse conditions, potentially promoting cancer progression.
  • CD4 down-regulation's role in this resistance requires further investigation.
  • Certain drugs, like alkylating agents, may overcome this specific type of drug resistance.

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