Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid

Akira Yoshiyama; Takeshi Morii; Kouki Ohtsuka; Hiroaki Ohnishi; Takashi Tajima; Takayuki Aoyagi; Kazuo Mochizuki; Kazuhiko Satomi; Shoichi Ichimura

Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid

Anticancer Res. 2016 Feb;36(2):625-31.

Authors

Akira Yoshiyama¹, Takeshi Morii², Kouki Ohtsuka³, Hiroaki Ohnishi³, Takashi Tajima⁴, Takayuki Aoyagi¹, Kazuo Mochizuki¹, Kazuhiko Satomi¹, Shoichi Ichimura¹

Affiliations

¹ Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
² Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan t-morii@gb3.so-net.ne.jp.
³ Department of Clinical Laboratory Medicine, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan.
⁴ Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan Department of Drug Design Proteome Area of Research, National Cancer Research Center Research Institute, Tsukiji, Chuuo-ku, Tokyo, Japan.

PMID: 26851017

Abstract

Background: Drug resistance is closely related to cancer cell stemness, that is acquired along with resistance to various anticancer agents. However, this has not been investigated as a potential mechanism underlying cancer cell resistance to zoledronate, that is used to suppress bone metastasis.

Materials and methods: Zoledronate-resistant A549 lung cancer and MG63 osteosarcoma cell lines were established by repeated treatment with sub-lethal concentrations of zoledronate. Expression levels of the stem cell marker NANOG, cMYC, octamer-binding transcription factor 4, and sex-determining region Y-box 2 were evaluated and sphere formation was compared between parental and resistant cell lines. Tumourigenicity was assessed in vivo.

Results: Stem cell marker expression was up-regulated and sphere formation was enhanced in resistant compared to parental cells and showed greater tumour formation capacity in mice.

Conclusion: Repeated treatment of malignant tumour cell lines with zoledronate, induces the development of drug resistance and stemness.

Keywords: Osteosarcoma; cancer stem cells; drug resistance; lung cancer; zoledronic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Biomarkers, Tumor / metabolism
Blotting, Western
Bone Density Conservation Agents / pharmacology
Bone Neoplasms / drug therapy
Bone Neoplasms / pathology*
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / pathology*
Cell Proliferation / drug effects
Diphosphonates / pharmacology*
Drug Resistance, Neoplasm / drug effects*
Humans
Imidazoles / pharmacology*
Lung Neoplasms / drug therapy
Lung Neoplasms / pathology*
Male
Mice
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / pathology*
Osteosarcoma / drug therapy
Osteosarcoma / pathology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Zoledronic Acid

Substances

Biomarkers, Tumor
Bone Density Conservation Agents
Diphosphonates
Imidazoles
Zoledronic Acid