Serotonin Analogues as Inhibitors of Breast Cancer Cell Growth

  • ACS Med Chem Lett. 2017 Sep 14;8(10):1072-1076. doi: 10.1021/acsmedchemlett.7b00282.
Jiney Jose  1  2 ,  Clint D J Tavares  1  3 ,  Nancy D Ebelt  1  3 ,  Alessia Lodi  4 ,  Ramakrishna Edupuganti  1  2 ,  Xuemei Xie  5  6 ,  Ashwini K Devkota  1  3 ,  Tamer S Kaoud  1 ,  Carla L Van Den Berg  3  7 ,  Eric V Anslyn  2 ,  Stefano Tiziani  4 ,  Chandra Bartholomeusz  5  6 ,  Kevin N Dalby  1  3
Affiliations
  • 1. Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, United States.
  • 2. Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
  • 3. Graduate Program in Cell and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, United States.
  • 4. Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas 78723, United States.
  • 5. Section of Translational Breast Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 6. Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 7. Division of Pharmacology & Toxicology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, Texas 78723, United States.
PMID: 29057053 DOI: 10.1021/acsmedchemlett.7b00282
Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a critical local regulator of epithelial homeostasis in the breast and exerts its actions through a number of receptors. Dysregulation of serotonin signaling is reported to contribute to breast Cancer pathophysiology by enhancing cell proliferation and promoting resistance to Apoptosis. Preliminary analyses indicated that the potent 5-HT1B/1D serotonin receptor agonist 5-nonyloxytryptamine (5-NT), a triptan-like molecule, induced cell death in breast Cancer cell lines. Thus, we synthesized a series of novel alkyloxytryptamine analogues, several of which decreased the viability of various human Cancer cell lines. Proteomic and metabolomic analyses showed that compounds 6 and 10 induced Apoptosis and interfered with signaling pathways that regulate protein translation and survival, such as the Akt/mTOR pathway, in triple-negative breast Cancer cells.

Keywords
Breast cancer; serotonin receptor; tryptamine.