Combination of Bevacizumab and Acyclic Retinoid Inhibits the Growth of Hepatocellular Carcinoma Xenografts

Abstract

SummaryThe prognosis of patients with hepatocellular carcinoma (HCC) is poor and the development of effective treatments for this malignancy, including combination chemotherapy, is required. This study examined the possible combined inhibitory effects of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and acyclic retinoid (ACR), which can prevent the development of HCC, on the growth of Huh7 human HCC cells. Xenograft tumors were produced by subcutaneously injecting Huh7 cells into nude mice. Starting 1 wk after the tumor cell injection, the mice were treated with bevacizumab alone (5 mg/kg body weight, subcutaneous injection, twice a week), ACR alone (given in a diet containing 0.03%), or their combination for 6 wk, and the effects of these regimens on xenograft growth were examined. Combined treatment with bevacizumab plus ACR significantly suppressed the growth of Huh7 xenografts. The combination of these agents significantly inhibited the phosphorylation of the Akt protein in tumor tissues. With combination therapy, the population of Ki-67-positive cells in xenografts decreased, while that of TUNEL-positive cells increased. The combination of bevacizumab and ACR exerts growth-suppressing effects on HCC cells by inhibiting cell proliferation and inducing apoptosis. This combination might be an effective regimen for the treatment of HCC.

Dicer Enhances Bevacizumab-Related Inhibition of Hepatocellular Carcinoma via Blocking the Vascular Endothelial Growth Factor Pathway

“…Several preclinical studies did suggest that the use of bevacizumab in combination with other agents may be a choice for HCC treatment. 64 We found that calcitriol inhibited the growth of gastric cancer cells by inducing Dicer expression, 65 however a suitable concentration of calcitriol should be assessed and validated preclinically in HCC xenografts.…”

Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats

“…ACR and ARB have been demonstrated to exert multiple pharmacological activities for efficiently preventing hepatocarcinogenesis. Similar to ARB, ACR also commonly exerts synergistic effects in combination with other clinically available drugs, including interferon-β, valproic acid, vitamin K2, trastuzumab, and bevacizumab [ 48 – 51 ]. In addition to these agents, recent xenograft analysis has demonstrated that branched-chain amino acids (BCAA) may also be used as a candidate partner for peretinoin-based cocktail therapy against HCC [ 35 ].…”