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

Abstract

Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumorinitiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G 2 -M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrateresistant prostate cancer.

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis

“…We therefore investigated whether darinaparsin (S-dimethylarsino-glutathione), a novel arsenic-based drug with a favorable systemic toxicity profile (43) and currently undergoing clinical studies in hematologic malignancies and solid tumors (35,36), inhibits the Hh effectors GLI1 and GLI2 and affects the proliferation of MSC-like cells in vitro. Indeed, darinaparsin was recently shown to modulate GLI protein levels in prostate cancer cell lines (44).…”

“…Darinaparsin is currently being tested in phase 2 clinical trials for solid tumors and hematopoietic malignancies; however, its molecular mechanism of action has not been fully elucidated (51). It has been reported that ATO antagonizes both GLI1 and GLI2 (41,42), and a very recent report also suggests that darinaparsin might reduce GLI2 protein levels in prostate tumor-initiating cells (44).…”

CUL4B regulates cancer stem‐like traits of prostate cancer cells by targeting BMI1 via miR200b/c

“…CSCs have self‐renewal, multidirectional differentiation, and strong tumorigenesis ability . Classical signal pathways relating to CSCs including Wnt, Notch, Hedgehog, and PI3K/AKT pathways . Recently, increasing evidence suggested that epigenetic modifications play a crucial role in regulating stem cell characteristics .…”

To wake up cancer stem cells, or to let them sleep, that is the question

“…A recent study showed that As 2 O 3 sensitizes CSC‐like cells of human glioblastoma multiforme to the c‐Myc inhibitor 10058‐F4 and that the combination of these two compounds induced the regression of such tumors formed in immunodeficient mice . Similarly, the combination of darinaparsin, an organic derivative of As 2 O 3 , and docetaxel was found to inhibit the growth of tumors formed by human prostate cancer cell lines in vivo by targeting of CSCs …”