Stage‐specific effect of N‐(4‐hydroxyphenyl)retinamide on cell growth in squamous cell carcinogenesis

Abstract

Squamous cell carcinoma (SCC) is the most prevalent form of epithelial cancer. SCC results when normal epithelial cells undergo multiple neoplastic changes that culminate in the evolution of an invasive cancer. Retinoids are commonly used as chemopreventive and treatment agents in skin cancer; however, SCC progression is accompanied by a gradual loss of retinoid responsiveness. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) has shown promising anti-neoplastic activity in a variety of tumor cells, including those that are resistant to all-trans retinoic acid (t-RA). We investigated the effect of HPR on growth and apoptosis of squamous cells at different stages of carcinogenesis. We then determined if retinoic acid receptor (RAR) overexpression affected the outcome of HPR treatment. To model SCC malignant progression, we used a panel of murine keratinocytes representing different stages of squamous cell carcinogenesis. This panel consisted of primary keratinocytes, SP1 and 308 papilloma cell lines, the PAM-212 squamous carcinoma cell line, and the spindle I7 cell line. With the exception of the primary keratinocytes, all cells were unresponsive to t-RA treatment. Pharmacological concentrations of HPR were non-cytotoxic to all keratinocytes tested and HPR sensitivity was stage-dependent, with the papilloma cell lines being the most sensitive, and the spindle cells being the most resistant. Overexpression of RARgamma in SP1 papilloma cells enhanced growth suppression and apoptosis induction by HPR. HPR-induced growth suppression was accompanied by a simultaneous block in the G(1) phase of the cell cycle in RAR-transduced and control SP1 cells and differential regulation of cell cycle and apoptotic mediators.

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

“…a stimulation. Although fenretinide has inhibited the proliferation of many tumor cell lines (7)(8)(9)(10)(11), it has been shown to have minimal cytotoxicity to nonmalignant cells ( 7,12 ). In our study, fenretinide (2.5-5 M) did not induce toxicity in Raw 264.7 cells after up to 16 h treatment (n = 4; P > 0.05; data not shown), which confi rmed that fenretinide had minimal cytotoxicity.…”

“…Fenretinide has been widely used in clinical trials for breast cancer chemoprevention ( 5 ) and for treatment of neuroblastoma and Ewing sarcoma ( 6 ). It has been shown that fenretinide inhibits the proliferation of many tumor cell lines (7)(8)(9)(10)(11), whereas it manifests minimal cytotoxicity to nonmalignant cells ( 7,12 ). Early studies of fenretinide supported the hypothesis that fenretinide increased the de novo synthesis of ceramide by stimulating SPT (13)(14)(15).…”

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

“…Alternatively, the morphological effects after ligand-activation of overexpressed RARg may indicate a transition to a cell phenotype where apoptosis is a consequence of retinoic acid treatment, as has been reported for S-type neuroblastoma cells. 14 In contrast to recent results for squamous carcinoma cells, 15 RARg overexpression did not significantly affect fenretinide-induced apoptosis, and this suggests that RARg activation by fenretinide does not have a major role in apoptosis of neuroblastoma cells. One possibility is that, despite its minor contribution to RAR-RXR heterodimers in these cells, 7 RARb may be involved in apoptosis.…”

Cell death induced by N‐(4‐hydroxyphenyl)retinamide in human epidermal keratinocytes is modulated by TGF‐β and diminishes during the progression of squamous cell carcinoma

“…The potential of 4‐HPR as a chemopreventive agent has been demonstrated in a variety of different cell types,17 and in clinical trials it has been shown that 4‐HPR can protect against ovarian cancer, inhibit the recurrence of premalignant oral lesions and inhibit the recurrence of breast cancer in premenopausal women 11, 12, 41. Examination of the effects of 4‐HPR on keratinocytes derived from the skin, however, is limited and relates to studies that have used either cell lines of murine origin42, 43 or genetically unrelated human squamous carcinoma cell lines23, 44 and one preliminary clinical trial in which topically applied 4‐HPR caused regression of the premalignant skin lesion actinic keratoses 45. The present study examined the effects of 4‐HPR on human skin‐derived epidermal keratinocytes in vitro .…”