Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis

Abstract

Dehydroepiandrosterone (DHEA) inhibits the development of early pre-neoplastic lesions and prevents tumor development in various tissues when given to animals during the initiation/promotion stages of carcinogenesis. Our purpose was to evaluate whether DHEA can also arrest the growth and progression of late lesions, such as persistent nodules (PNs) of rat liver. Male F344 rats were subjected to initiation by diethylnitrosamine followed by selection according to the "resistant hepatocyte" (RH) protocol. Fifteen weeks after initiation, when PNs were present in the liver, the rats were fed a diet with/without 0.6% DHEA for a maximum of 15 weeks. Glucose-6-phosphate dehydrogenase (G6PD) activity was 17- to 20-fold higher in PNs than in normal liver 15-30 weeks after initiation. It significantly decreased, in both liver and PNs, 16 hr after starting DHEA feeding. Further DHEA feeding for 3-15 weeks decreased G6PD activity by 55-58% in both tissues. Eight weeks after starting DHEA, a fall in the proportion of labeled cells, after continuous contact with 3H thymidine for 7 days, was found in nodules. Treatment for 15 weeks with DHEA caused a marked decrease in the number of nodules per liver, as well as in the incidence of PNs with diameters of 3-6 and > 6 mm, respectively, while it did not affect PNs with diameters < 3 mm. Nodules showing patterns of malignant transformation were present in 40% of rats not treated with DHEA, but not in DHEA-treated rats. All of 8 surviving rats not treated with DHEA had carcinomas at the 56th week, while only 1 out of 4 surviving rats treated with DHEA had carcinoma. These data indicate that DHEA inhibits G6PD activity in rat liver and in PNs in vivo. This is associated with growth restraint of PNs and results in inhibition of their progression to malignancy.

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

“…DHEA gained special interest in cancer research because of its anticarcinogenic properties proven in various organs of laboratory rats including the liver (34,35,43; summarized in 7,19). Conversely, DHEA showed unfavorable effects in rat liver such as hepatomegaly and peroxisome proliferation, and after long-term treatment hepatocellular carcinomas developed (10,24,31,32,33).…”

Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice

“…G6PD activity was found to increase upon stimulation by growth factors in fibroblasts (Stanton et al, 1991), adipocytes (Teruel et al, 1996), and hepatocytes (Yoshimoto et al, 1983). The induction of G6PD activity was also detected in the tumors of several animal models of carcinogenesis, including diethylnitrosamineinduced liver tumors in rats (Simile et al, 1995) and estrogeninduced kidney tumors in hamsters (Roy and Liehr, 1988). Furthermore, a significant increase of G6PD activity was found in many naturally occurring tumors including breast carcinoma (Bokun et al, 1987), endometrial carcinoma (Hughes, 1976), cervical carcinoma (Dutu et al, 1980), prostatic carcinoma (Zampella et al, 1982), and lung tumors (Dessi et al, 1988).…”

The neuro-steroid, 3β androstene 17α diol exhibits potent cytotoxic effects on human malignant glioma and lymphoma cells through different programmed cell death pathways

“…Additionally, DHEA treatment has been shown to retard the onset of chemically induced cancers such as mammary, liver and prostate carcinogenesis in experimental rat models (Simile et al, 1995;Lubet et al, 1998;Rao et al, 1999). More recently, Yoshida et al (2003) reported that DHEA and its metabolites have antiproliferative effects on human hepatoma and human colonic adenocarcinoma cell lines.…”