PPAR activation and decreased proliferation in oral carcinoma cells with 4-HPR.
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.


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.


CONCLUSIONS
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.
Harris
George
G
Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Ghazallah
Raed Abu
RA
Nascene
David
D
Wuertz
Beverly
B
Ondrey
Frank G
FG
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects* / Q000378:metabolism*; D011336:Probability; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D047492:Peroxisome Proliferator-Activated Receptors; D017313:Fenretinide