Inhibition by N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid of exogenous and endogenous development of putative preneoplastic, glutathione S-transferase placental form-positive lesions in the livers of rats

Abstract

The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid (tRA) on the exogenous and endogenous models of rat liver carcinogenesis respectively using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the exogenous study, male Fischer 344 rats, 6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at week 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and killed at the end of week 8. For the endogenous study, rats were fed the CDAA diet containing 4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR decreased the numbers and sizes of the glutathione S-transferase placental form-positive foci, assayed as putative preneoplastic lesions, the levels of 8-hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the DEN-initiated case and, more prominently, in the CDAA diet-associated case. In contrast, while tRA failed to exert inhibitory effects apparently on foci development, 8-OHG formation or BrdU labeling in the DEN-initiated case, it reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by all three doses in the CDAA diet-associated case. Furthermore, both 4-HPR and tRA inhibited the CDAA diet-associated induction of hepatocyte necrosis and connective tissue increase but not intrahepatocellular fat accumulation. These results indicate that 4-HPR exerts chemopreventive effects against the exogenous and endogenous rat liver carcinogenesis, while tRA can inhibit only the latter.

Enhanced expression of growth factors and imbalance between hepatocyte proliferation and apoptosis in the livers of rats fed a choline-deficient, ?-amino acid-defined diet

“…Early changes in rats fed a CDAA diet are due to oxidative injury to DNA and other subcellular components and result in the elevation of serum ALT and liver triglyceride [27,28]. The most abundant oxidative DNA damage, caused by 8-hydroxydeoxyguanosine (8-OHdG), has previously been detected after 1 day of feeding the CDAA diet.…”

All-trans retinoic acid regulates hepatic bile acid homeostasis

“…Mice were treated with standard rodent chow or supplemented with all-trans RA (Sigma, St. Louis, MO) (150 mg/kg diet) for seven days. The concentration was chosen due to its anti-carcinogenic effect in a rat model of liver carcinogenesis in the absence of severe toxicity [28]. At the end of the treatment, mice were anesthetized with isoflurane and euthanized.…”

4-(N-Hydroxyphenyl)retinamide Can Selectively Induce Apoptosis in Human Epidermoid Carcinoma Cells But Not in Normal Dermal Fibroblasts

“…All-trans-N-(4-hydroxyphenyl)retinamide (4HPR), or fenretinide, not only inhibits cell proliferation but also can cause cell death by inducing apoptosis in certain cancer cells such as T lymphoma and T lymphoblastoid leukaemia cells (2), human breast cancer cells (3), small cell lung cancer cell lines (4), prostate adenocarcinoma cells (5), and head and neck squamous cell carcinoma (SCC) cells (6). The effectiveness of fenretinide as an anticancer drug was also confirmed using in vivo animal models (7)(8)(9) and it has now been entered into a number of clinical trials (10,11) in oncological diseases such as breast cancer, and bladder cancer mainly because of its promising anticancer properties, lack of genotoxicity, and fewer side effects compared to other retinoids (12). Because the skin is a well-known target tissue for retinoid action, various premalignant or malignant skin diseases, including actinic keratoses, basal cell carcinoma, and melanoma, have been tested for their response to retinoid treatment.…”