Fasting inhibits hepatic stellate cells activation and potentiates anti‐cancer activity of Sorafenib in hepatocellular cancer cells

Abstract

Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use.

Autophagy and intermittent fasting: the connection for cancer therapy?

“…Recently, studies in in vitro and in vivo models have shown that intermittent fasting improved the chemotherapeutic response to cisplatin, doxorubicin, cyclophosphamide 70 , oxaliplatin 71 , sorafenib 72 , mitoxantrone 73 , gemcitabine 74 , etoposide 75 , temozolomide 76 and tyrosine kinase inhibitors 77 in models of glioma, neuroblastoma, melanoma, fibrosarcoma and breast cancer, colon cancer, pancreatic cancer, hepatocellular cancer and lung cancer. IF has also been shown to improve the radiosensitivity of glioma 76 and breast cancer 78 in mice.…”

To fast, or not to fast before chemotherapy, that is the question

“…Fasting was shown to potentiate the efficacy of tyrosine kinase inhibitors by inhibiting the mitogen-activated protein kinase signaling pathway [ 7 ], and to synergize with Sorafenib in hampering hepatocellular carcinoma cell growth and glucose uptake, while normalizing the expression levels of genes commonly altered by Sorafenib itself [ 8 ].…”

Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line

“…Liver fibrosis is the final consequence of several types of chronic hepatic injuries, including viral hepatitis, alcohol abuse, drugs, metabolic diseases, autoimmune hepatitis, and congenital abnormalities (Czochra et al, ; Felver et al, ; Lo et al, ), resulting in liver chronic damage associated with the accumulation of fibrillar collagens and extracellular matrix proteins (ECM). In fact, after an acute or chronic liver damage, tissue regeneration repairs lesions with degradation of deposed fibrotic material, while mechanisms of tissue restoration are persistently activated following several repeated injuries, inducing deposition of ECM.…”