Abstract 4362: Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB)

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 15_Supplement; p. 4362
• Main Authors: Coulter, Don W., Vennerstrom, Jonathan, Sharp, John G., Dong, Yuxiang, Wang, Xiaofang, McIntyre, Erin, McGuire, Tim
• Format: Journal Article
• Language: English
• Published: 01.08.2015
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-4362

Abstract Introduction: NB is a pediatric tumor of neural crest origin. Patients who have N-MYC amplified metastatic tumors have poor outcomes. The importance of autophagy in protecting NB cells from chemotherapy has been postulated. In the following study we screened bisquinoline (BQ) and ozonide (OZ) antimalarials (potential autophagy inhibitors) in a highly N-MYC amplified NB cell line (BE-2) and a moderately amplified N-MYC NB cell line (IMR-32). A combination of monolayer cell culture and neurospheres were used to screen activity. Methods: Using a 96 well MMT based assay and 16 hour treatment with compounds dissolved in DMSO, cytotoxicity was calculated as a percent decline in absorbance compared to DMSO controls. 32 BQ and 13 OZ antimalarials were tested. All compounds were tested at a concentration of 1 mcg/ml; an achievable concentration in patients. Selected compounds that were cytotoxic in monolayer culture will be tested in neurosphere culture and then in a mouse xenograft model alone and combined with chemotherapy. Results: The bisquinolone antimalarials were consistently active in both BE-2 and IMR cell culture. Among the bisquinolones, Q1-9, Q2-5, Q2-61, and Q3-75 had the greatest cytotoxicity. There was no clear structure-activity-relationship for this small bisquinoline library. Among the ozonides, OZ465, OZ513, and OZ521 were the most active. From these data, we could infer that the presence of a weak base functional group was required, but was insufficient for cytotoxicity. Initial studies in BE-2 and IMR neurosphere culture using an LDH assay for cytotoxicity suggests similar activity. Monolayer results are shown in the Table below: SymbolDrug ClassBE-2*IMR-32*Q1-9BQ38.535.8Q2-5BQ29.844.4Q2-61BQ40.731.4Q3-75BQ40.619.3OZ465OZ3820.6OZ513OZ73.627.7OZ521OZ4415.9 *Percent decline in absorbance compared to DMSO control Conclusion: The above data indicates that two classes of antimalarials had moderate cytotoxicity in both 96-well monolayer assays as well as in a neurosphere assay (data not shown). The results suggest cytotoxic activity in high and moderately amplified N-MYC NB in both monolayers and neurospheres. Note: This abstract was not presented at the meeting. Citation Format: Don W. Coulter, Jonathan Vennerstrom, John G. Sharp, Yuxiang Dong, Xiaofang Wang, Erin McIntyre, Tim McGuire. Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB). [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 4362. doi:10.1158/1538-7445.AM2015-4362