Keywords
topsentinol L trisulfate, AMPK, CHK1, breast cancer, drug susceptibility
Abstract
Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers. We identified a previously unreported trisulfated sterol, i.e., topsentinol L trisulfate (TLT), which exhibited increased efficacy against BL-CL breast cancers relative to luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL cell lines revealed its ability to inhibit activation of AMP-activated protein kinase (AMPK) and checkpoint kinase 1 (CHK1) and to promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive.
Original Publication Citation
El-Chaar NN, Smith TE, Shrestha G, Piccolo SR, Harper MK, Van Wagoner RM, Lu Z, Venancio AR,Ireland CM, Bild AH, and Moos PJ. Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers Marine Drugs, 2021, 19(1).
BYU ScholarsArchive Citation
El-Chaar, Nader N.; Smith, Thomas E.; Shrestha, Gajendra; Piccolo, Stephen R.; Harper, Mary Kay; Van Wagoner, Ryan M.; Lu, Zhenyu; Venancio, Ashlee R.; Ireland, Chris M.; Bild, Andrea H.; and Moos, Philip J., "Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers" (2021). Faculty Publications. 7486.
https://scholarsarchive.byu.edu/facpub/7486
Document Type
Peer-Reviewed Article
Publication Date
2021-01-18
Publisher
MDPI
Language
English
College
Life Sciences
Department
Biology
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