CHM-1, a novel microtubule-destabilizing agent exhibits antitumor activity via inducing the expression of SIRT2 in human breast cancer cells

  • Chem Biol Interact. 2018 Jun 1;289:98-108. doi: 10.1016/j.cbi.2018.04.007.
Chin-Wei Liu  1 ,  Ying-Chao Lin  2 ,  Chao-Ming Hung  3 ,  Bing-Lan Liu  4 ,  Sheng-Chu Kuo  5 ,  Chi-Tang Ho  6 ,  Tzong-Der Way  7 ,  Chih-Hsin Hung  8
Affiliations
  • 1. Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan.
  • 2. Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan; Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan.
  • 3. Department of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, I-Shou University, Kaohsiung, Taiwan.
  • 4. Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan.
  • 5. School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
  • 6. Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
  • 7. Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan. Electronic address: [email protected].
  • 8. Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan. Electronic address: [email protected].
PMID: 29679549 DOI: 10.1016/j.cbi.2018.04.007
Abstract

Breast Cancer is a major public health problem throughout the world. In this report, we investigated whether CHM-1, a novel synthetic antimitotic agent could be developed into a potent antitumor agent for treating human breast Cancer. CHM-1 induced growth inhibition in MDA-MB-231, MDA-MB-453 and MCF-7 cells in a concentration-dependent manner. Importantly, CHM-1 is less toxic to normal breast (HBL-100) cells. CHM-1 interacted with tubulin, markedly inhibited tubulin polymerization, and disrupted microtubule organization. Proteins from control and CHM-1-treated animal tumor specimens were analyzed by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Our results indicated that CHM-1 increased the expression of SIRT2 protein, an NAD-dependent tubulin deacetylase. A prodrug strategy was also investigated to address the problem of low aqueous solubility and low bioavailability of the antitumor agent CHM-1. The water-soluble prodrug of CHM-1 (CHM-1-P) was synthesized. After oral and intravenous administration, CHM-1-P induced a dose-dependent inhibition of tumor growth. The aforementioned excellent anti-tumor activity profiles of CHM-1 and its prodrug CHM-1-P, suggests that CHM-1-P deserves to further develop as a clinical trial candidate for treating human breast carcinoma.

Keywords
Antimitotic agent; CHM-1; Prodrug; SIRT1; SIRT2.
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