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Arsenic trioxide circumvents multidrug resistance based on different mechanisms in human leukemia cell lines

Tamami Seo1, Yoshimasa Urasaki, Haruyuki Takemura

  • 1First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.

Anticancer Research
|May 5, 2005
PubMed

Insights

Arsenic trioxide (As2O3) shows antitumor effects against multidrug-resistant leukemia cells. Glutathione levels influence sensitivity, and combining As2O3 with buthionine-sulfoximine enhances efficacy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Multidrug resistance (MDR) is a major challenge in leukemia treatment.
  • Specific resistance mechanisms include overexpression of p-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP1), as well as altered expression of anti-apoptotic proteins like Bcl-2.
  • Novel therapeutic agents are needed to overcome MDR in leukemia.

Purpose of the Study:

  • To evaluate the antitumor activity of arsenic trioxide (As2O3) against human leukemia cell lines with distinct multidrug resistance mechanisms.
  • To investigate the role of intracellular glutathione (GSH) and Pgp/MRP1 expression in mediating sensitivity or resistance to As2O3.
  • To explore the potential of combining As2O3 with buthionine-sulfoximine (BSO) to enhance its efficacy in MDR leukemia.

Main Methods:

  • Utilized three human leukemia cell lines: K562/D1-9 (Pgp-overexpressing, daunorubicin-resistant), HL60/AD (MRP1-overexpressing, daunorubicin and Ara-C resistant), and 697/Bcl-2 (Bcl-2 transfected).
  • Assessed cellular sensitivity to As2O3.
  • Measured intracellular glutathione (GSH) content and investigated the effect of GSH depletion using buthionine-sulfoximine (BSO).

Main Results:

  • Arsenic trioxide (As2O3) demonstrated antitumor effects across all three tested multidrug-resistant leukemia cell lines.
  • K562/D1-9 cells exhibited collateral sensitivity to As2O3, while HL60/AD cells showed minor cross-resistance.
  • Intracellular glutathione (GSH) content was identified as a critical factor in As2O3 sensitivity; BSO-mediated GSH depletion enhanced As2O3 efficacy and overcame MRP1-related resistance in HL60/AD cells.

Conclusions:

  • Arsenic trioxide (As2O3) is effective against diverse multidrug-resistant leukemia cell lines.
  • Glutathione (GSH) levels significantly impact the sensitivity of leukemia cells to As2O3.
  • Combination therapy with As2O3 and buthionine-sulfoximine (BSO) holds promise for treating multidrug-resistant leukemia by enhancing As2O3 sensitivity and overcoming resistance mechanisms.

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