Biotransformation and protein binding of N-(4-hydroxyphenyl)retinamide in murine mammary epithelial cells

Bunk, M. J.; Kinahan, James J.; Sarkar, Nurul H.

doi:10.1016/0304-3835(85)90056-4

Cited by 11 publications

(8 citation statements)

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“…These laboratory studies have provided strong evidence that retinoids, functioning as antiproliferative and differentiation-inducing agents, affect the promotional stage of carcinogenesis to inhibit chemical carcinogen-induced tumor development (14)(15)(16)(17)(18)(19). Data generated using in vitro models developed from mammary explant and cell culture systems have suggested that retinoids inhibit preneoplastic transformation via multiple mechanisms, which are dependent on the specific target tissue and the type of retinoid (33,(35)(36)(37)(38). The laboratory data generated from in vivo and in vitro models are dependent on extrapolation for their clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

“…The data generated by these experiments clearly demonstrated that co-treatment of cells with HPR ϩ NAC resulted in substantial reduction of HPR-induced apoptosis, and treatment with HPR alone resulted in time-dependent increases in the formation of the biologically inert metabolite MPR and in the extent of cellular apoptosis. Previous studies on rodent and human mammary tissue have demonstrated that HPR is preferentially sequestered in the epithelial and adipocyte cells and is subject to metabolism by the transformation sensitive target tissue (7,33,34,37,55). Our current data on 184-B5/HER cells support these previous observations by demonstrating that human mammary epithelial at Pennsylvania State University on February 21, 2013 http://carcin.oxfordjournals.org/ Downloaded from cells are metabolically competent to convert HPR to MPR and that biological consequence of metabolic process is the induction of apoptosis in HPR responsive cells.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide

Jinno

Steiner²,

Mehta

et al. 1999

Carcinogenesis

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Epithelial cells from non-cancerous mammary tissue in response to exposure to chemical carcinogens or transfection with oncogenes exhibit hyperproliferation and hyperplasia prior to the development of cancer. Aberrant proliferation may, therefore, represent a modifiable early occurring preneoplastic event that is susceptible to chemoprevention of carcinogenesis. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR), has exhibited preventive efficacy in several in vitro and in vivo breast cancer models, and represents a promising chemopreventive compound for clinical trials. Clinically relevant biochemical and cellular mechanisms responsible for the chemopreventive effects of HPR, however, are not fully understood. Experiments were performed on preneoplastic human mammary epithelial 184-B5/HER cells derived from reduction mammoplasty and initiated for tumorigenic transformation by overexpression of HER-2/neu oncogene, to examine whether HPR inhibits aberrant proliferation of these cells and to identify the possible mechanism(s) responsible for the inhibitory effects of HPR. Continuous 7-day treatment with HPR produced a dose-dependent, reversible growth inhibition. Long-term (21 day) treatment of 184-B5/HER cells with HPR inhibited anchorage-dependent colony formation by approximately 80% (P < 0.01) relative to that observed in the solvent control. A 24 h treatment with cytostatic 400 nM HPR produced a 25% increase (P = 0.01) in G0/G1 phase, and a 36% decrease (P = 0.01) in S phase of the cell cycle. HPR treatment also induced a 10-fold increase (P = 0.02) in the sub-G0 (apoptotic) peak that was down-regulated in the presence of the antioxidant N-acetyl-L-cysteine. Treatment with HPR resulted in a 30% reduction of cellular immunoreactivity to tyrosine kinase, whereas immunoreactivity to p185HER remained essentially unaltered. HPR exposure resulted in time-dependent increase in cellular metabolism of the retinoid as evidenced by increased formation of the inert metabolite N-(4-methoxyphenyl)-retinamide (MPR) and progressive increase in apoptosis. Thus, HPR-induced inhibition of aberrant proliferation may be caused, in part, by its ability to inhibit HER-2/neu-mediated proliferative signal transduction, retard cell cycle progression and upregulate cellular apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide

Jinno

Steiner²,

Mehta

et al. 1999

Carcinogenesis

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“… 37 While 4‐HPR possesses actions as a retinoid, such growth inhibition and induction of differentiation and apoptosis 71 is without dependence on classical retinoic acid and retinoid X receptors, and it is thus more efficient than conventional retinoids. 72 It also inhibits cyclo‐oxygenases and prostaglandin synthesis. 73 Similarly, non‐steroidal anti‐inflammatory drugs (NSAID) having the potential to inhibit COX2, acetylsalicylic acid (ASA) and piroxicam (PXC), exert almost the same effects as 4‐HPR ( Table 2).…”

Section: Prevention Of Liver Carcinogenesis In Rats Fed the Cdaa Dietmentioning

confidence: 99%

Endogenous liver carcinogenesis in the rat *

Nakae

1999

Pathology International

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Carcinogenesis may be effected not only through exposure to exogenous stimuli but also by genetic and epigenetic influences derived from endogenous factors. In the latter case, the mechanisms are still largely obscure because of the limited availability of appropriate in vivo experimental models. However, continuous feeding of a diet deficient in choline and methionine is well known to cause hepatocellular carcinomas (HCC) in rats in the absence of any known exogenous carcinogens and can serve as a good research model. A semi-synthetic, choline-deficient, L-amino acid-defined (CDAA) diet, containing practically no choline and low methionine, induces HCC with a background of fatty liver and hepatocyte death, subsequent regeneration and fibrosis resulting in cirrhosis. Using the CDAA diet, we have revealed the participation of oxidative injury to DNA and other subcellular components and of alteration in intrahepatic signal transduction pathways in the mechanisms underlying this rat liver carcinogenesis model. In the present paper, the current understanding of endogenous rat liver carcinogenesis, due to dietary choline deficiency, is reviewed.

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“…45) In the present experiment, we studied the effects of tRA, one physiologically active retinoid and 4-HPR, which is less toxic than tRA, and acts independently of the retinoid receptor. 46) The present finding of inhibition of HPD cell proliferation but unchanged MK mRNA expression by tRA and 4-HPR, thus, suggests a disturbance in the upregulation mechanisms in hamster PC cells. β-Carotene, which is a precursor of retinoic acid, exerts chemopreventive effects on pancreatic carcinogenesis in hamsters, 47) but this clearly might not involve regulation of MK expression.…”

Section: Discussionmentioning

confidence: 46%

Overexpression of Midkine in Pancreatic Duct Adenocarcinomas Induced by N‐Nitrosobis(2‐oxopropyl)amine in Hamsters and Their Cell Lines

Tsutsumi

Kadomatsu

Tsujiuchi

et al. 2000

Japanese Journal of Cancer Research

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Biotransformation and protein binding of N-(4-hydroxyphenyl)retinamide in murine mammary epithelial cells

Cited by 11 publications

References 11 publications

Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide

Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide

Endogenous liver carcinogenesis in the rat *

Overexpression of Midkine in Pancreatic Duct Adenocarcinomas Induced by N‐Nitrosobis(2‐oxopropyl)amine in Hamsters and Their Cell Lines

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