MDPI: Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma (Houghton Lab)

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Saikat Haldar
Hongyan Ma
Victoria M. Anderson
Ross D. Overacker
April L. Risinger,
Sandra Loesgen
Peter J. Houghton
Robert H. Cichewicz
Susan L. Mooberry

Ewing sarcoma is a cancer of the bone and soft tissues that affects children and adolescents. Unfortunately, only 20–30% of patients with metastatic Ewing sarcoma survive, necessitating the need to identify new, more effective therapies. We screened natural product extracts from plants and fungal cultures to identify compounds with selective cytotoxic activity against Ewing sarcoma cells, which led to the identification of altertoxin II as a compound with highly selective activity against Ewing sarcoma cells. Mechanism of action studies showed that altertoxin II selectively induces DNA damage in Ewing sarcoma cells, but does not bind to DNA. Additionally, we found that altertoxin II has antitumor activity in a mouse model of Ewing sarcoma, suggesting it will be useful as a lead compound to help identify new molecular targets for the development of new Ewing-sarcoma-specific therapies.
A screening program designed to identify natural products with selective cytotoxic effects against cell lines representing different types of pediatric solid tumors led to the identification of altertoxin II as a highly potent and selective cytotoxic against Ewing sarcoma cell lines. Altertoxin II, but not the related compounds altertoxin I and alteichin, was highly effective against every Ewing sarcoma cell line tested, with an average 25-fold selectivity for these cells as compared to cells representing other pediatric and adult cancers. Mechanism of action studies revealed that altertoxin II causes DNA double-strand breaks, a rapid DNA damage response, and cell cycle accumulation in the S phase. Our studies also demonstrate that the potent effects of altertoxin II are partially dependent on the progression through the cell cycle because the G1 arrest initiated by a CDK4/6 inhibitor decreased antiproliferative potency more than 10 times. Importantly, the cell-type-selective DNA-damaging effects of altertoxin II in Ewing sarcoma cells occur independently of its ability to bind directly to DNA. Ultimately, we found that altertoxin II has a dose-dependent in vivo antitumor efficacy against a Ewing sarcoma xenograft, suggesting that it has potential as a therapeutic drug lead and will be useful to identify novel targets for Ewing-sarcoma-specific therapies.

 

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