(2e-4e-6e-10e)-3-7-11-15-tetramethyl-2-4-6-10-14-hexadecapentaenoic-acid and Cell-Transformation--Neoplastic

Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes.. Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs).. OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment.. ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.

Topics: Angiotensin Receptor Antagonists; Animals; Biomarkers; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Diethylnitrosamine; Disease Models, Animal; DNA Damage; Drug Synergism; Humans; Lipid Peroxidation; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Oxidative Stress; Protective Agents; Rats; Rats, Inbred OLETF; Tretinoin

In an attempt to develop effective and non-cytotoxic cancer chemopreventive derivatives of retinoids, a novel acyclic retinoid has previously been synthesized. This acyclic retinoid, NIK-333, had been reported to suppress recurrence of primary hepatocellular carcinomas. We explored the molecular mechanisms by which NIK-333 exerts anti-proliferative effects.. We employed Balb/c 3T3 cells, since they can be used as a quantitative transformation assay and since we can study a possible involvement of gap-junctional intercellular communication (GJIC) in their growth control. We included all-trans-retinoic acid (ATRA) for comparison.. We first confirmed that these cells express the retinoid receptors, RARalpha, gamma and RXRalpha, suggesting that they respond to NIK-333 and ATRA. When NIK-333 or ATRA was added to Balb/c 3T3 cells during the induction of cell transformation by a standard (3-methylcholanthrene (MCA) alone) or two-stage (low dose of MCA plus 12-O-tetradecanoylphorbol-13-acetate (TPA)) protocol, there was a significant decrease in the number of transformed foci. The extent of inhibition of transformation by NIK-333 was similar to that exerted by ATRA. Employing the microinjection dye-transfer assay, we found that both retinoids increase GJIC level when measured 24h after treatment. The extent of GJIC increase by NIK-333 was similar to that of ATRA. These retinoids also increased the amount of connexin 43 (Cx43) on the plasma membrane as revealed by immunostaining.. These data indicate that NIK-333 suppresses chemical carcinogenesis in vitro and support the hypothesis that enhancement of GJIC is involved in this process.

Topics: Animals; BALB 3T3 Cells; Cell Communication; Cell Transformation, Neoplastic; Connexin 43; Gap Junctions; Mice; Retinoids; Tretinoin

Many patients with liver cirrhosis are in a state of protein and energy malnutrition and require careful nutritional support. Our research has revealed that approximately 30% of the patients have protein-energy malnutrition, 40% protein malnutrition, and 10% energy malnutrition; 20% are in a normal nutritional state. Supplementation with branched-chain amino acids alleviates chronic liver failure, improves the protein nutritional state, and subsequently prolongs survival. In contrast, therapeutic modalities for energy malnutrition have not yet been fully elucidated and await further studies. Improved survival of the cirrhotic patients essentially brings a higher incidence of hepatocellular carcinoma (HCC). A synthetic analogue of vitamin A (acyclic retinoid or 4,5-dehydrogeranyl geranoic acid) prevents at least the development of second primary tumors after curative treatment of preceding HCC. The mechanism of this cancer chemo-prevention is clonal deletion of premalignant and latent malignant cells by the retinoid. We describe our clinical experiences with these two nutritional pharmacotherapies of chronic liver diseases and review their basic mechanisms.

Topics: Amino Acids, Branched-Chain; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Combined Modality Therapy; Humans; Liver Cirrhosis; Liver Failure; Liver Neoplasms; Nutritional Support; Protein-Energy Malnutrition; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; Tretinoin

Topics: Carcinoma, Hepatocellular; Carrier State; Cell Transformation, Neoplastic; DNA, Viral; Hepatitis B virus; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Retinoids; Tretinoin

E-5166 is a newly synthesized polyprenoic acid that has been reported to control epithelial differentiation and to have antiproliferative effects on various tumor cells in vitro. This study examined the effects of E-5166 on the proliferation of keratinocytes. Three kinds of keratinocytes were used: normal human keratinocytes, a human trichilemmoma-derived K-TL-1 cell line, and a Pam 212 cell line. Cell proliferation was measured by 3H-thymidine incorporation and also by determining cell numbers. E-5166 was found to have significant antiproliferative effects on each of the cell lines studied. When Pam 212 cells were cultured in the presence of E-5166, cell proliferation was inhibited in a dose-dependent fashion. The inhibitory effect appeared to be reversible, since removal of E-5166 from the culture medium resulted in a subsequent return of cell proliferation. For normal human keratinocytes and K-TL-1 cells, E-5166 inhibited 3H-thymidine incorporation in a dose-dependent fashion. Furthermore, E-5166 showed significantly stronger antiproliferative capacity than Ro 10-9359, one of the aromatic retinoids, on Pam 212 cells and normal human keratinocytes.

Topics: Animals; Cell Division; Cell Line; Cell Line, Transformed; Cell Transformation, Neoplastic; Humans; Keratinocytes; Male; Mice; Tretinoin

Using C3H/10T-1/2 mouse fibroblasts, we tested whether polyprenoic acid (E-5166) inhibits radiogenic and chemically induced transformation in vitro. Our results show that E-5166 markedly inhibits transformation by X rays and benzo[a]pyrene in a dose-related manner. Maximum inhibition was observed when cells were pretreated with E-5166 prior to carcinogen exposure, and lesser inhibition when E-5166 treatment followed carcinogen exposure. These results indicate that E-5166 can serve as a radio-protective and chemopreventive agent with anticarcinogenic potential.

Topics: Animals; Antineoplastic Agents; Benzo(a)pyrene; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Fibroblasts; Mice; Tretinoin