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PPARα activation can help prevent and treat non-small cell lung cancer

Nataliya Skrypnyk1, Xiwu Chen, Wen Hu

  • 1Authors' Affiliations: Departments of Medicine, Division of Nephrology, Cancer Biology, and Biochemistry, Vanderbilt University; Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee; and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.

Cancer Research
|December 5, 2013
PubMed

Insights

Targeting epoxyeicosatrienoic acids (EETs) formation via cytochrome P450 arachidonic acid epoxygenases (Cyp2c) offers a novel treatment for non-small cell lung cancer (NSCLC). Activating PPARα with bezafibrate safely reduced NSCLC growth and angiogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-small cell lung cancer (NSCLC) poses a significant mortality risk, particularly when inoperable, due to limitations in current chemotherapy.
  • There is a critical need for novel, effective, and safe therapeutic strategies against NSCLC.

Purpose of the Study:

  • To investigate targeting the synthesis of proangiogenic epoxyeicosatrienoic acids (EETs) by cytochrome P450 arachidonic acid epoxygenases (Cyp2c) as a therapeutic strategy for NSCLC.
  • To evaluate the efficacy of activating the transcription factor PPARα using ligands like bezafibrate and Wyeth-14,643 in preclinical NSCLC models.

Main Methods:

  • Utilized transgenic murine K-Ras and human orthotopic models of NSCLC.
  • Administered PPARα activators (bezafibrate, Wyeth-14,643) to downregulate Cyp2c44 expression.
  • Assessed primary and metastatic tumor growth, angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels.

Main Results:

  • PPARα activation by bezafibrate and Wyeth-14,643 effectively downregulated Cyp2c44.
  • Treatments significantly reduced primary and metastatic NSCLC growth and tumor angiogenesis.
  • Beneficial effects on tumor growth and angiogenesis were durable, persisting after drug withdrawal and independent of treatment timing.

Conclusions:

  • Downregulating Cyp2c expression or activity presents a promising, safe, and effective therapeutic avenue for NSCLC.
  • Bezafibrate, a clinically approved drug for lipidemia, offers a potential agent for clinical trials in human lung cancer treatment due to its safety and efficacy profile.

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