Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model

Abstract

BackgroundCancer stem cells (CSCs) play a key role in the posthepatectomy recurrence of hepatocellular carcinoma (HCC). CD133+ HCC cells exhibit liver CSC–like properties, and CSC differentiation–inducing therapy may lead these cells to lose their self-renewal ability and may induce terminal differentiation, which may in turn allow their malignant potential to be controlled. Because arsenic trioxide (As2O3) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As2O3 might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs.MethodsWe evaluated the As2O3 induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As2O3 on recurrence rates and median survival in a mouse xenograft model.ResultsWe found that As2O3 induced HCC CSC differentiation by down-regulating the expression of CD133 and some stemness genes, thus inhibiting the cells’ self-renewal ability and tumorigenic capacity without inhibiting their proliferation in vitro. In vivo experiments indicated that As2O3 decreased recurrence rates after radical resection and prolonged survival in a mouse model. As2O3, which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1.ConclusionsWe found that As2O3 induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As2O3 should be further evaluated.

Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma

“…Moreover, As 2 O 3 suppresses angiogenesis by inhibiting vascular endothelial growth factor (VEGF) . Recent studies also indicate that As 2 O 3 is capable of inhibiting liver CSCs . Nevertheless, the clinical safety and utility of As 2 O 3 have not yet been fully clarified.…”

Arsenic trioxide nanoparticles inhibit acute promyelocytic leukemia cell proliferation and induce apoptosis via PTEN/AKT signalling pathway

“…As 2 O 3 , a kind of traditional Chinese medicine, had been approved as frontline treatment for APL by FDA for many years. It could also be used in other solid cancer, such as liver cancer, prostate cancer, cervical cancer and breast cancer [9,[12][13][14][15][16][17][18]. However, its clinical application is somehow limited owing to its high toxicity to the normal tissues.…”

Inhibition of the Cancer Stem Cells-Like Properties by Arsenic Trioxide, Involved in the Attenuation of Endogenous Transforming Growth Factor Beta Signal

“…After 4 weeks, the mice were sacrificed, and the tumor tissues were removed for further investigation. A, Tumor volumes were calculated using the formula: induces the CSCs differentiation in pancreatic cancer, gliomas, glioblastoma, and HCC, in the molecular mechanisms, the blockage of signal transduction induced by Notch or GLI1 are involved Wu et al, 2013;Zhang et al, 2014;Zhen et al, 2010). In addition, As 2 O 3 modifies the expressions of a serial of miRNAs, such as miR-98, miR-30, miR-210, and miR-200 c, which are involved in the regulation of differentiation and self-renewal (Gao et al, 2014;Meng et al, 2011;Si et al, 2014;Yang et al, 2014).…”

“…Further, as a model agent, As 2 O 3 causes significant vascular shutdown in brain, liver, breast, and gastric cancers (Alhasan et al, 2012;Jiang et al, 2014b). Recent studies reveal a novel function of As 2 O 3 that it depletes the CSCs population or induces the CSCs differentiation in pancreatic cancer, gliomas, glioblastoma, as well as HCC Wu et al, 2013;Zhang et al, 2014;Zhen et al, 2010). However, the molecular mechanisms involved in remain unclear.…”