Altertoxin ii, a highly effective and specific compound against ewing sarcoma

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 cytotoxin 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‐typeselective 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.

Original languageEnglish (US)
Article number6176
JournalCancers
Volume13
Issue number24
DOIs
StatePublished - Dec 1 2021

Keywords

  • Drug discovery
  • Ewing sarcoma
  • Fungal secondary metabolites
  • Natural products
  • Soil microbes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Altertoxin ii, a highly effective and specific compound against ewing sarcoma'. Together they form a unique fingerprint.

Cite this