Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells

Toyotaka Iguchi, Yoshitaka Miyakawa, Kaori Saito, Chika Nakabayashi, Makoto Nakanishi, Hideyuki Saya, Yasuo Ikeda, Masahiro Kizaki

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Osteosarcoma is one of the most common primary malignant tumors of the bone in children and adolescents. Some patients continue to have a poor prognosis, as they have metastatic disease and frequent occurrence of drug resistance. Zoledronate is a nitrogen-containing bisphosphonate that has been used for the treatment of hypercalcemia and bone metastasis, because it induces apoptosis in osteoclasts and tumor cells by inhibiting the isoprenylation of intracellular small G proteins. Besides inhibiting isoprenylation, little is known about the manner by which bisphosphonates inhibit cellular proliferation and induce apoptosis. This prompted us to investigate the inhibitory effects of zoledronate in human osteosarcoma cell lines, HOS and MG63. HOS cells accumulated in S phase around 6 h after treatment with 10 μM zoledronate, followed by apoptosis. When HOS cells were treated with zoledronate, ATM kinase and its substrate, check-point kinase (Chk)1, were phosphorylated. Zoledronate also induced phosphorylation of cdc25a (Thr506) in HOS cells, which is a substrate of Chk1, and its phosphorylation is known to be critical for S phase arrest. Following treatment with zoledronate, phosphorylated histone H2AX (γ-H2AX) displayed patterns of nuclear foci in HOS cells. As γ-H2AX accumulates at dsDNA breaks, these results demonstrate that zoledronate induced DNA damage and S phase arrest, accompanied by activation of the ATM/Chk1/cdc25 pathway in a human osteosarcoma cell line.

Original languageEnglish
Pages (from-to)285-291
Number of pages7
JournalInternational Journal of Oncology
Volume31
Issue number2
Publication statusPublished - 2007 Aug

Fingerprint

zoledronic acid
Osteosarcoma
S Phase
DNA Damage
Apoptosis
Prenylation
Diphosphonates
Phosphotransferases
Phosphorylation
Bone and Bones
Cell Line
Monomeric GTP-Binding Proteins
Hypercalcemia
Osteoclasts
Drug Resistance
Histones
Neoplasms

Keywords

  • ATM
  • Check-point kinase
  • Osteosarcoma
  • S phase arrest
  • Zoledronate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells. / Iguchi, Toyotaka; Miyakawa, Yoshitaka; Saito, Kaori; Nakabayashi, Chika; Nakanishi, Makoto; Saya, Hideyuki; Ikeda, Yasuo; Kizaki, Masahiro.

In: International Journal of Oncology, Vol. 31, No. 2, 08.2007, p. 285-291.

Research output: Contribution to journalArticle

Iguchi, Toyotaka ; Miyakawa, Yoshitaka ; Saito, Kaori ; Nakabayashi, Chika ; Nakanishi, Makoto ; Saya, Hideyuki ; Ikeda, Yasuo ; Kizaki, Masahiro. / Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells. In: International Journal of Oncology. 2007 ; Vol. 31, No. 2. pp. 285-291.
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