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Fractionated irradiation can induce functionally relevant multidrug resistance gene and protein expression in human

Dirk Bottke1, Daniel Koychev, Antonia Busse

  • 1University Hospital Ulm, Department of Radiotherapy, 89081 Ulm, Germany. dirk.bottke@uniklinik-ulm.de

Radiation Research
|June 28, 2008
PubMed

Insights

Fractionated irradiation enhances multidrug resistance (MDR)-associated proteins like P-glycoprotein (P-gp) and lung resistance-related protein (LRP) in cancer cells. This upregulation leads to increased resistance to chemotherapy drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • The molecular mechanisms underlying radiotherapy-induced multidrug resistance (MDR) remain incompletely understood.
  • Multidrug resistance-associated proteins, including P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), are implicated in MDR.

Purpose of the Study:

  • To investigate the impact of fractionated irradiation on the expression of MDR-associated proteins (P-gp, MRP, LRP) and their corresponding mRNAs.
  • To assess the functional consequences of irradiation-induced changes in protein expression on cancer cell sensitivity to chemotherapy.

Main Methods:

  • Six colon and five breast cancer cell lines were subjected to fractionated irradiation (27 Gy total dose, 1.8 Gy/fraction/week).
  • Messenger RNA (mRNA) expression was quantified using quantitative RT-PCR.
  • Protein levels and drug sensitivity to cisplatin, doxorubicin, and bendamustine were determined via flow cytometry.

Main Results:

  • Breast cancer cell lines exhibited enhanced mRNA expression for P-gp, MRP1, and LRP post-irradiation.
  • Colon cancer cell lines showed significant upregulation of P-gp, MRP, and LRP proteins after irradiation.
  • Irradiated cell lines demonstrated increased resistance to cisplatin, doxorubicin, and bendamustine compared to controls.

Conclusions:

  • Fractionated irradiation upregulates MDR-associated proteins P-gp and MRP, confirming known mechanisms of MDR.
  • Radiation-induced enhancement of LRP presents a novel mechanism contributing to multidrug resistance in cancer cells.

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