Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling.

Abstract

Chemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization.

• Authors: Luqi Wang, Yue Wang, Andy Chen, Aydin Jalali, Shengzhi Liu, Yunxia Guo, Sungsoo Na, Harikrishna Nakshatri, Bai-Yan Li, Hiroki Yokota
• Journal: International journal of oncology (Int J Oncol) Vol. 53 Issue 3 Pg. 1001-1012 (Sep 2018) ISSN: 1791-2423 [Electronic] Greece
• PMID: 30015873 (Publication Type: Journal Article)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Carbazoles
• PD 407824
• Protein Kinase Inhibitors
• TP53 protein, human
• Thiophenes
• Tumor Suppressor Protein p53
• Urea
• Checkpoint Kinase 2
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1

Topics

• Animals
• Bioprinting (methods)
• Bone Remodeling (drug effects, physiology)
• Bone and Bones (cytology, diagnostic imaging, drug effects, physiology)
• Calcification, Physiologic (drug effects)
• Carbazoles (pharmacology)
• Cell Culture Techniques
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1 (antagonists & inhibitors)
• Checkpoint Kinase 2 (antagonists & inhibitors)
• Down-Regulation
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Neoplasms (drug therapy, pathology)
• Osteoblasts (drug effects, physiology)
• Osteoclasts (drug effects, physiology)
• Osteogenesis (drug effects)
• Printing, Three-Dimensional
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• RAW 264.7 Cells
• Spheroids, Cellular
• Thiophenes (pharmacology, therapeutic use)
• Tumor Suppressor Protein p53 (metabolism)
• Urea (analogs & derivatives, pharmacology, therapeutic use)
• X-Ray Microtomography