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The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1

R Abdul-Ghani1, V Serra, B Györffy

  • 1Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité, Universitätsmedizin Berlin, Schumannstr, D-10117 Berlin, Germany.

Oncogene
|November 17, 2005
PubMed

Insights

The phosphoinositol-3-kinase (PI3K) inhibitor LY294002 enhances doxorubicin efficacy in colon cancer cells by blocking drug export and promoting apoptosis, suggesting potential for treating multidrug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer is a significant challenge, often involving membrane transporters and altered cell survival pathways.
  • Mitogenic signaling pathways, including Ras and phosphoinositol-3-kinase (PI3K/Akt), are implicated in MDR.
  • Targeting these pathways offers a potential strategy to overcome drug resistance.

Purpose of the Study:

  • To investigate if inhibiting PI3K/Akt signaling sensitizes drug-resistant colon cancer cells to cytotoxic drugs.
  • To determine the mechanism by which PI3K inhibitors affect drug resistance and intracellular drug accumulation.

Main Methods:

  • Drug-resistant HT29RDB colon cancer cells were treated with doxorubicin in combination with PI3K inhibitors (LY294002) or Mek inhibitors (PD98059, U0126).
  • Apoptosis levels, Akt phosphorylation, intracellular doxorubicin concentration, and drug efflux were measured.
  • Drug efflux inhibition was compared to known multidrug resistance-associated protein 1 (MRP1) inhibitors.

Main Results:

  • Cotreatment with doxorubicin and LY294002 induced massive apoptosis, unlike Mek inhibitors.
  • LY294002 blocked Akt phosphorylation and increased intracellular doxorubicin concentration threefold.
  • LY294002 competitively inhibited doxorubicin export, with efficacy comparable to MRP1 inhibitors.

Conclusions:

  • The PI3K/Akt pathway plays a crucial role in cell survival and MDR in HT29RDB colon cancer cells.
  • The PI3K inhibitor LY294002 demonstrates therapeutic potential in combination with doxorubicin for treating MRP1-mediated drug resistance.

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