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Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein

O A Patutina1, N L Mironova, E B Logashenko

  • 1Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.

Bulletin of Experimental Biology and Medicine
|July 18, 2012
PubMed

Insights

High-dose cyclophosphamide can overcome resistance in RLS lymphosarcoma by inducing apoptosis. Suppressing mdr1a/1b genes with small interfering RNA (siRNA) enhanced cyclophosphamide

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RLS lymphosarcoma exhibits high expression of mdr1a and mdr1b genes, which encode P-glycoprotein.
  • This P-glycoprotein expression confers resistance to low-dose cyclophosphamide treatment.
  • RLS lymphosarcoma is sensitive to high doses of cyclophosphamide, approaching maximum tolerated doses.

Purpose of the Study:

  • To investigate the efficacy of high-dose cyclophosphamide in RLS lymphosarcoma.
  • To explore the role of mdr1a/1b gene expression in cyclophosphamide resistance.
  • To evaluate the therapeutic potential of suppressing mdr1a/1b genes using small interfering RNA (siRNA).

Main Methods:

  • Cytofluorometry and electrophoresis were used to demonstrate apoptotic cell death.
  • RLS(40) tumor cells with enhanced mdr1a/1b gene expression were utilized.
  • Simultaneous suppression of mdr1a/1b genes was achieved using specific small interfering RNA (siRNA).

Main Results:

  • High doses of cyclophosphamide induced apoptotic death in RLS cells.
  • Therapeutic effects of cyclophosphamide were significantly increased when mdr1a/1b genes were suppressed by siRNA.
  • This suggests that the active metabolite of cyclophosphamide may be a substrate for P-glycoprotein.

Conclusions:

  • High-dose cyclophosphamide is effective against RLS lymphosarcoma by inducing apoptosis.
  • Targeting mdr1a/1b genes with siRNA can enhance the efficacy of cyclophosphamide therapy.
  • P-glycoprotein plays a role in mediating cyclophosphamide resistance in RLS lymphosarcoma.

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