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PPAR activation and decreased proliferation in oral carcinoma cells with 4-HPR
George Harris1, Raed Abu Ghazallah, David Nascene
1Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Objective:
To explore whether the mechanism of action of 4-hydroxyphenylretinamide (4-HPR, fenretidine), a synthetic retinoid, involves the functional activation of the nuclear hormone receptor class known as PPARs (peroxisome proliferator-activated receptors). Also, to examine whether anti-proliferative effects of this agent in head and neck cancer cells occur at biologically relevant concentrations.
Study Design/Methods:
CA 9-22, NA, and UM SCC 11B cells were treated with 4-HPR during their log phase growth and functional activation of PPAR gamma was evaluated by plate luminometry. Cellular proliferation was analyzed by standard MTT cell proliferation assays and cell counting. Student's t tests were performed for all experiments.
Results:
Significant dose-dependent increases in PPAR gamma activation occurred in response to 4-HPR treatment. Proliferation was significantly inhibited by 4-HPR in a dose-dependent manner as judged by MTT and cell counting assays. These effects occurred at equimolar concentrations in both types of experiments within a range of clinically achievable doses (1-4 microM) of 4-HPR.
Conclusions:
4-HPR can functionally activate PPAR gamma at clinically achievable doses. Decreased cancer cell proliferation secondary to PPAR gamma activation has been observed in other malignancies as well as upper aerodigestive cancer. PPAR gamma activation by 4-HPR represents another potential anti-cancer mechanism of action for this drug.
Clinical Significance:
PPAR gamma activation represents a novel target for anti-cancer therapy for head and neck cancer and the current level of clinical toxicity of 4-HPR would be judged acceptable to utilize this agent alone or in combination chemotherapy.
Insights
Fenretidine (4-HPR) activates PPAR gamma, inhibiting head and neck cancer cell proliferation at clinically relevant doses. This PPAR gamma activation offers a potential new anti-cancer strategy.
Area of Science:
- Molecular biology
- Cancer research
- Pharmacology
Background:
- Synthetic retinoids like 4-hydroxyphenylretinamide (4-HPR, fenretidine) are investigated for anti-cancer properties.
- The nuclear hormone receptor peroxisome proliferator-activated receptors (PPARs) play roles in cellular processes relevant to cancer.
Purpose of the Study:
- To determine if 4-HPR activates PPARs, specifically PPAR gamma.
- To assess the anti-proliferative effects of 4-HPR on head and neck cancer cells at biologically relevant concentrations.
Main Methods:
- Head and neck cancer cell lines (CA 9-22, NA, UM SCC 11B) were treated with 4-HPR.
- PPAR gamma activation was measured using plate luminometry.
- Cell proliferation was assessed via MTT assays and cell counting.
Main Results:
- 4-HPR treatment resulted in significant, dose-dependent activation of PPAR gamma.
- Cell proliferation was significantly inhibited by 4-HPR in a dose-dependent manner.
- These effects were observed at clinically achievable concentrations (1-4 microM).
Conclusions:
- 4-HPR functionally activates PPAR gamma at clinically relevant doses.
- PPAR gamma activation by 4-HPR presents a potential anti-cancer mechanism for head and neck cancers.
- PPAR gamma activation is a promising therapeutic target for head and neck cancer, with acceptable toxicity for fenretidine.
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