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.
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.
Authors: Dušan Garić; Juan B De Sanctis; Gabriella Wojewodka; Daniel Houle; Shanon Cupri; Asmahan Abu-Arish; John W Hanrahan; Marian Hajduch; Elias Matouk; Danuta Radzioch Journal: J Mol Med (Berl) Date: 2017-07-10 Impact factor: 4.599
Authors: Donna E Seabloom; Arthur R Galbraith; Anna M Haynes; Jennifer D Antonides; Beverly R Wuertz; Wendy A Miller; Kimberly A Miller; Vernon E Steele; Mark Steven Miller; Margie L Clapper; M Gerard O'Sullivan; Frank G Ondrey Journal: Cancer Prev Res (Phila) Date: 2017-01-04
Authors: Maria J Worsham; Kang Mei Chen; Tamer Ghanem; Josena K Stephen; George Divine Journal: Otolaryngol Head Neck Surg Date: 2013-06-04 Impact factor: 3.497
Authors: Jeffrey A Hall; Mark Rusten; Raed D Abughazaleh; Beverly Wuertz; Vannesa Souksavong; Paul Escher; Frank Ondrey Journal: Head Neck Date: 2020-06-09 Impact factor: 3.147