Antitumoral Activity of Rapamycin Mediated Through Inhibition of HIF-1alpha and VEGF in Hepatocellular Carcinoma

Abstract

Rapamycin (RAPA) inhibits tumor growth and angiogenesis in hepatocellular carcinoma (HCC). The molecular mechanism underlying the antitumoral effects of RAPA remains unclear. Here we established a chemical-induced rat HCC model to investigate the signaling pathways mediating RAPA's antitumor activity. We found that RAPA exposure significantly diminished tumor growth, angiogenesis, and metastasis of HCC. Meanwhile, the antitumor drug dramatically decreased expression of HIF-1alpha and VEGF, either at mRNA or protein levels. Moreover, the low-dose of RAPA (1.5 mg/kg/day) was effective enough to markedly inhibit tumor progression of HCC. The preliminary results suggested that the antitumoral effects of RAPA might be at least partially mediated through downregulation of HIF-1alpha and VEGF, and low-dose RAPA-based regimens exhibited a promising future in treatment of HCC.

Modulation of hypoxia-inducible factors (HIF) from an integrative pharmacological perspective

“…mTOR is positioned as an upstream activator of HIF and the mTOR inhibitor rapamycin inhibits HIF-1a-dependent transcription induced by hypoxia [44], HIF-1a protein accumulation by inhibition of HIF-1a protein synthesis [45], as well as promotion of HIF-1a protein degradation [44]. Rapamycin functions as an anticancer agent by regulating HIF activity in the liver [46] and in kidney cancer cell lines and mouse models [47]. The recently discovered HIF inhibitor FM19G11 can impair HRE-mediated trans-activation mediated by HIF as well as down-regulating HIFa proteins under hypoxic conditions.…”

Estrogen Suppresses Metastasis in Rat Hepatocellular Carcinoma through Decreasing Interleukin-6 and Hepatocyte Growth Factor Expression

“…In order to evaluate the effects and the underlying molecular mechanisms of estrogen on HCC metastasis, we examined two pro-inflammatory cytokines which are largely responsible for the hepatic response to infections or systemic inflammation in acute or chronic liver infection, interleukin-6 (IL-6), and hepatocyte growth factor (HGF), in our established in vivo HCC model induced by diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR) [6].…”

Future Therapies of Wet Age-Related Macular Degeneration

“…Sirolimus is used to prevent rejection after organ transplantation, particularly after renal transplantation [15]. Sirolimus markedly inhibits response of vascular endothelial cells to stimulation by VEGF [16] and inhibits hypoxia-inducible factor-1 α , a major upstream regulator of VEGF [17]. In a murine AMD model, systemic administration of sirolimus inhibited both choroidal and retinal neovascularization [18, 19].…”