Abstract 4215: Small molecule compounds that destabilize stem cell factors

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Cancer stem cells (CSCs) are thought to be present in malignant tumors at various proportions, and their phenotype can drift over time. Based on the current view, this elusive population of cancer cells is likely responsible for distant metastases, drug resistance and recurrence. However, the process by which such cell population is generated and maintained in a tumor mass has been unclear. Based on our previous study (PNAS Vol. 110: 6097-102 2013) and others, this process may involve the elevated expression of stem cell factors (SOX2, OCT4, NANOG, LIN28, KLF4, MYC, MYCN and those with equivalent functions). If so, it is conceivable that destabilization of these proteins would facilitate the eradication of CSC compartments in tumor mass. We have previously identified several small molecule compounds that confer the anti-growth effect on the stem cell-like neuroblastoma cells via screening of the Prestwick Chemical Library®, containing 1200 FDA-approved small molecules and of other selected experimental small molecules by using MTS assays. These compounds were structurally and biologically diverse molecules, including Alexidine (Alex), Benzethonium (Benz), Ketoconazole (Keto), Flubendazole (Flu), Auranofin (Aura), Nifuroxazide (Nif), Itraconazole (Itac) and JQ1. In this study, we investigated the effects of these selected small molecules on the expression of stem cell factors using the human teratocarcinoma cell lines NT2 and NCCIT as model systems, because these cells retain the expression of the majority of stem cell factors. The teratocarcinoma cell lines were treated with the small molecules at 0.5 to 10 μM for 24 hours and subjected to Western blot analysis. The expression of stem cell factors was down-regulated in NT2 cells by the several small molecules tested. The expression of SOX2 was down-regulated by Benz (5 μM), Flu (10 μM), Nif (10 μM), Aura (1 μM) and JQ1 (5 μM); the expression of OCT4 was down-regulated by Benz, Flu, Nif, Alex and JQ1; the NANOG expression was down-regulated by the all compounds tested; the expression of LIN28 was down-regulated by Benz, Flu and Aura; the expression of MYC/MYCN was down-regulated by Benz, Flu, Nif, Alex, Keto and JQ1. Interestingly, Auranofin treatment augmented the expression of MYC/MYCN, although the compound was growth suppressive to NT2 cells. Unlike the stem cell factors, the expression of LIN28B, which is the homologue of LIN28, was not affected by any of the compounds tested. A similar observation was made for NCCIT cells, but the effect of the compounds on the expression of stem cell factors appeared to be weaker. Collectively, the data suggest that small molecules identified via the process described could become useful lead chemicals for developing drug-like compounds that can target the most malignant stem cell-like cancer cells. Citation Format: Naohiko Ikegaki, Sarah Lomahan, Xao Tang. Small molecule compounds that destabilize stem cell factors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4215. doi:10.1158/1538-7445.AM2015-4215