Evaluation of the antiproliferative effects of the HASPIN inhibitor CHR-6494 in breast cancer cell lines.

Abstract

HASPIN is a serine/threonine kinase that regulates mitosis by phosphorylating histone H3 at threonine 3. The expression levels of HASPIN in various cancers are associated with tumor malignancy and poor survival, suggesting that HASPIN inhibition may suppress cancer growth. As HASPIN mRNA levels are elevated in human breast cancer tissues compared with adjacent normal tissues, we examined the growth-suppressive effects of CHR-6494, a potent HASPIN inhibitor, in breast cancer cell lines in vitro and in vivo. We found that HASPIN was expressed in breast cancer cells of all molecular subtypes, as well as in immortalized mammary epithelial cells. HASPIN expression levels appeared to be correlated with the cell growth rate but not the molecular subtype of breast cancer. CHR-6494 exhibited potent antiproliferative effects against breast cancer cell lines and immortalized mammary epithelial cells in vitro, but failed to inhibit the growth of MDA-MB-231 xenografted tumors under conditions that have significant effects in a colorectal cancer model. These results imply that CHR-6494 does have antiproliferative effects in some situations, and further drug screening efforts are anticipated to identify more potent and selective HASPIN inhibition for use as an anticancer agent in breast cancer patients.

• Authors: Hisayo Nishida-Fukuda, Keizo Tokuhiro, Yukio Ando, Hiroaki Matsushita, Morimasa Wada, Hiromitsu Tanaka
• Journal: PloS one (PLoS One) Vol. 16 Issue 4 Pg. e0249912 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 33852630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(1H-indazol-5-yl)-N-propylimidazo(1,2-b)pyridazin-6-amine
• Indazoles
• Intracellular Signaling Peptides and Proteins
• Pyridazines
• RNA, Messenger
• HASPIN protein, human
• Protein Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Indazoles (pharmacology, therapeutic use)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Nude
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Pyridazines (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• Transplantation, Heterologous