Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists

Abstract

SUMMARY Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMOD477G, confer resistance to these inhibitors. We report here that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMOD477G medulloblastoma.

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

“…In addition, ATO caused a reduction of overall levels of Gli2. Moreover, in SMO inhibitor-resistant cells, ATO efficiently inhibited tumor growth either alone or in combination with itraconazole, a compound that also inhibited Shh signaling (16). In this study, we show that darinaparsin also inhibited Shh signaling.…”

Repurposing itraconazole as an anticancer agent

“…Itraconazole inhibits AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling in human umbilical vein endothelial cells (HUVECs), glioblastoma, endometrial carcinoma (EC) and melanoma cells (10)(11)(12)(13)(14). Inhibition of Hedgehog signaling was observed in basal cell carcinoma, medulloblastoma, pleural mesothelioma, breast cancer and melanoma cells (9,(14)(15)(16)(17), but not in EC cells (13). Inhibition of Wnt/β-catenin signaling was observed in basal cell and examined in melanoma cells (14).…”

MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma

“…Analogous rapid responses of medulloblastoma and BCC to treatment with vismodegib were reported in clinical trials (39). However, the appearance of drug -resistant tumors after an initially rapid response to vismodegib in a patient with metastatic medulloblastoma, underscored the need for alternative drugs against SMO or other pathway components (18,27), and in fact, several preclinical studies have begun using combinations of SMO inhibitors with PI3K/mTOR inhibitors or arsenic trioxide and itraconazole (40)(41)(42) In this study, we show that Gli1 expression, the most sensitive marker of Hh pathway activity, is strongly inhibited by MK-4101, both in medulloblastoma and BCC tumors. Mechanistically, cDNA microarray analysis of gene expression profiles in response to MK-4101 revealed a strong downregulation of genes involved in cell-cycle control, such as those regulating cell-cycle progression at G 1 -S, including E2F2, cyclin D1 (CCND1), cyclin E2 (CCNE2), and CDK2.…”