Inhibitory Effect of the HASPIN Inhibitor CHR-6494 on BxPC-3-Luc, A Luciferase-Expressing Pancreatic Cancer Cell Line

Document Type : Short Communication

Authors

1 Faculty of Pharmaceutical Sciences, Nagasaki International University, Huis Ten Bosch, Sasebo, Nagasaki, Japan

2 Department of Genome Editing, Institute of Biomedical Science, Kansai Medical University, Shin-machi, Hirakata City, Osaka, Japan

Abstract

HASPIN acts in chromosome segregation via histone phosphorylation. Recently, HASPIN inhibitors have been shown 
to suppress growth of various cancer cells. Pancreatic cancer has no symptom in the early stages and may progress 
before detection. So, the 5-year survival rate is low. Here, we reported that administration of the HASPIN inhibitor, 
CHR-6494, to mice bearing pancreatic BxPC-3-Luc cancer cells significantly suppressed growth of BxPC-3-Luc cells. 
CHR-6494 might be a useful agent for treating pancreatic cancer.  

Keywords


  1. Tanaka H, Yoshimura Y, Nozaki M, Yomogida K, Tsuchida J, Tosaka Y, et al. Identification and characterization of a haploid germ cellspecific nuclear protein kinase (Haspin) in spermatid nuclei and its effects on somatic cells. J Biol Chem. 1999; 274(24): 17049- 17057.
  2. Dai J, Sultan S, Taylor SS, Higgins JM. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 2005; 19(4): 472- 488.
  3. Hada M, Kim J, Inoue E, Fukuda Y, Tanaka H, Watanabe Y, Okada Y. TH2A is phosphorylated at meiotic centromere by Haspin. Chromosoma. 2017; 126(6): 769-780.
  4. Shimada M, Goshima T, Matsuo H, Johmura Y, Haruta M, Murata K, et al. Essential role of autoactivation circuitry on Aurora B-mediated H2AX-pS121 in mitosis. Nat Commun. 2016; 7: 12059.
  5. Huertas D, Soler M, Moreto J, Villanueva A, Martinez A, Vidal A, et al. Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin. Oncogene. 2012; 31(11):1408-1418.
  6. Tanaka H, Wada M, Park J. HASPIN kinase inhibitor CHR-6494 suppresses intestinal polyp development, cachexia, and hypogonadism in Apcmin/+ mice. Eur J Cancer Prev. 2020; 29(6): 481- 485.
  7. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014; 74: 2913–2921.
  8. Brunner M, Wu Z, Krautz C, Pilarsky C, Grützmann R, Weber GF. Current clinical strategies of pancreatic cancer treatment and open molecular questions. Int J Mol Sci. 2019; 20(18): 4543.
  9. Maiolica A, de Medina-Redondo M, Schoof EM, Chaikuad A, Villa F, Gatti M, et al. Modulation of the chromatin phosphoproteome by the HASPIN protein kinase. Mol Cell Proteomics. 2014; 13(7): 1724–1740.
  10. Amoussou NG, Bigot A, Roussakis C, Robert JH. HASPIN: A promising target for the design of inhibitors as potent anticancer drugs. Drug Discov Today. 2018; 23(2): 409–415.
  11. Opoku-Temeng C, Dayal N, Aflaki Sooreshjani M, Sintim HO. 3Hpyrazolo[ 4,3-f]quinoline HASPIN kinase inhibitors and anticancer properties. Bioorg Chem. 2018; 78: 418–426.
  12. Bastea LI, Hollant LMA, Döppler HR, Reid EM, Storz P. Sangivamycin and its derivatives inhibit HASPIN-Histone H3-survivin signaling and induce pancreatic cancer cell death. Sci Rep. 2019; 9(1): 16588.
  13. Melms JC, Vallabhaneni S, Mills CE, Yapp C, Chen JY, Morelli E, et al. Inhibition of HASPIN kinase promotes cell-intrinsic and extrinsic antitumor activity. Cancer Res. 2020; 80(4): 798–810.
  14. Kim JE, Lee SY, Jang M, Choi HK, Kim JH, Chen H, et al. Coumestrol epigenetically suppresses cancer cell proliferation: Coumestrol is a natural HASPIN kinase inhibitor. Int J Mol Sci. 2017; 18(10): 2228.
  15. Moura DS, Campillo-Marcos I, Vázquez-Cedeira M, Lazo PA. VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis. Cell Mol Life Sci. 2018; 75(14): 2591–2611.
  16. Han X, Kuang T, Ren Y, Lu Z, Liao Q, Chen W. HASPIN knockdown can inhibit progression and development of pancreatic cancer in vitro and vivo. Exp Cell Res. 2019; 385(1): 111605.