Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: Chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched‐chain amino acids

Abstract

The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy.

Pentoxifylline prevents nonalcoholic steatohepatitis-related liver pre-neoplasms by inhibiting hepatic inflammation and lipogenesis

“…In the state of obesity and/or diabetes, adipokine (adipocytokine) imbalances and insulin resistance are believed to play an important role in the development of malignancies, including liver cancer, which are shown in both human and rodent studies (El-Serag et al, 2004;Imai et al, 2010;Shimizu et al, 2011Shimizu et al, , 2014Watanabe et al, 2011). In the present study, adiponectine, leptin, fasting glucose, and insulin levels in serum were examined and the homeostasis model assessment-insulin resistance was calculated, but they showed no statistically significant differences between PTX-treated and control groups (data no shown).…”

Hepatic stellate cells as key target in liver fibrosis

“…Retinoid receptor signaling in hepatocytes is implicated in liver carcinogenesis, and a synthetic acyclic retinoid, peretinoin, has been assessed as a potential cancer chemoprevention measure [227, 228]. In HSCs, all-trans retinoic acid (ATRA) (an RAR ligand) moderately inhibits expression of procollagen I, III, IV, fibronectin, laminin, αSMA, TGFβ, and IL-6, but with no effect on cell proliferation, whereas 9-cis (RXR ligand) moderately inhibits proliferation without affecting the fibrogenic gene expression in rodents [229, 230].…”

Associations of branched-chain amino acids with parameters of energy balance and survival in colorectal cancer patients: results from the ColoCare study

“…There is evidence regarding BCAA-induced apoptosis in cancer cells (Terakura et al 2012; Shimizu et al 2014) and inhibition of angiogenesis. (Murata and Moriyama 2007; Cha et al 2013) Using a summary risk score we observed that patients in the top tertile had a significant 4-fold increase of risk of death compared to patients in the bottom tertile.…”

“…Prior studies have shown BCAA-induced apoptosis (Terakura et al 2012; Shimizu et al 2014) and inhibition of angiogenesis in cancer cells. (Murata and Moriyama 2007; Cha et al 2013).…”