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Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents

M A Ihnat1, J P Lariviere, A J Warren

  • 1Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|August 1, 1997
PubMed

Insights

Genotoxic chemicals, like mitomycin C, can suppress P-glycoprotein, a key factor in multidrug resistance. This suppression enhances cancer cell sensitivity to chemotherapy, offering new treatment strategies for resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • P-glycoprotein overexpression is a primary mechanism of multidrug resistance in cancer.
  • Genotoxic chemicals, especially DNA cross-linking agents, can alter gene expression at the transcriptional level.
  • The mdr1 gene, encoding P-glycoprotein, is known to be highly inducible.

Purpose of the Study:

  • To investigate the effects of genotoxic chemotherapy agents on P-glycoprotein expression.
  • To explore the potential of modulating multidrug resistance using DNA cross-linking agents.

Main Methods:

  • Treatment of various human and rodent cancer cell lines (colon, breast, leukemia, neuroblastoma, hepatoma) with subtoxic doses of DNA cross-linking agents (mitomycin C, cisplatin, BMS181174, chromium(VI)).
  • Assessment of P-glycoprotein mRNA and protein expression levels.
  • Measurement of drug efflux rates.
  • Evaluation of cancer cell sensitivity to P-glycoprotein substrates (e.g., doxorubicin) post-treatment.

Main Results:

  • Mitomycin C significantly suppressed P-glycoprotein mRNA and protein expression, reducing drug efflux.
  • Pretreatment with mitomycin C increased cancer cell sensitivity to doxorubicin by 5- to 10-fold.
  • Suppression of P-glycoprotein was observed with other DNA cross-linking agents (cisplatin, BMS181174, chromium(VI)) across diverse cell lines and culture conditions.

Conclusions:

  • Sub-chemotherapeutic doses of DNA cross-linking agents can effectively suppress P-glycoprotein expression, a key driver of multidrug resistance.
  • This modulation of the multidrug resistance phenotype offers a promising strategy for novel chemotherapy regimens targeting resistant tumors.
  • Combining DNA cross-linking agents with cytotoxic agents could overcome therapeutic resistance in various cancer types.

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