Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway

Abstract

The Hedgehog (Hh) pathway is activated in some human cancers, including medulloblastoma. The gliomaassociated oncogene homolog (GLI) transcription factors are critical mediators of the activated Hh pathway, and their expression may be elevated in some tumors independent of upstream Hh signaling. Thus, therapies targeting GLI transcription factors may benefit a wide spectrum of patients with mutations at different nodal points of the Hh pathway. In this study, we present evidence that arsenic trioxide (ATO) suppresses human cancer cell growth and tumor development in mice by inhibiting GLI1. Mechanistically, ATO directly bound to GLI1 protein, inhibited its transcriptional activity, and decreased expression of endogenous GLI target genes. Consistent with this, ATO inhibited the growth of human cancer cell lines that depended on upregulated GLI expression in vitro and in vivo in

Characteristics of doxorubicin-selected multidrug-resistant human leukemia HL‑60 cells with tolerance to arsenic trioxide and contribution of leukemia stem cells

“…As 2 O 3 has good curative effects and little cross-resistance with conventional chemotherapeutics (2,(17)(18)(19)(20)(21). Previous studies have revealed that conventional MDR leukemia cells exhibit increased sensitivity to As 2 O 3 instead of manifesting cross-resistance.…”

“…One potential explanation for this is that As 2 O 3 may not be a substrate of P-gp and may inhibit P-gp activity (2,(18)(19)(20)(21)(22). The present study selected HL-60 human promyelocyte leukemia cells for doxorubicin (ADM)-resistance by long-term exposure to intermittent and continuous stepwise increments of ADM, and characterized the distinguishing features of acquired MDR, particularly in terms of sensitivity to As 2 O 3 and the role of LSCs.…”

The Utility of Hedgehog Signaling Pathway Inhibition for Cancer

“…Further observations corroborate this finding; for instance, treatment of Ewing sarcoma family of tumors (ESFT) cell lines with ATO led to marked cytotoxicity and the presence of higher GLI1/2 expression seems to indicate increased sensitivity to ATO. Additionally, tumor growth in ESFT xenografts was inhibited with ATO administration; this treatment was associated with an increased survival in constitutively activated SMO transgenic mouse model for medulloblastoma (ND2:SmoA1), with significantly decreased GLI target gene expression [82].…”

Darinaparsin Inhibits Prostate Tumor–Initiating Cells and Du145 Xenografts and Is an Inhibitor of Hedgehog Signaling

“…Itraconazole, also inhibits Shh signaling by inhibiting downstream gli-2 transcription, such as ATO and darinaparsin, (16). In a phase II study, itraconazole showed only modest antitumor activity, and dose escalation was limited by toxicity (15).…”