Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma

Ayaka Morisawa; Tatsuo Okui; Tsuyoshi Shimo; Soichiro Ibaragi; Yuka Okusha; Mitsuaki Ono; Thi Thu Ha Nguyen; Nur Mohammad Monsur Hassan; Akira Sasaki

doi:10.3892/ijo.2018.4242

Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma

Int J Oncol. 2018 Mar;52(3):989-999. doi: 10.3892/ijo.2018.4242. Epub 2018 Jan 10.

Authors

Ayaka Morisawa¹, Tatsuo Okui¹, Tsuyoshi Shimo¹, Soichiro Ibaragi¹, Yuka Okusha², Mitsuaki Ono³, Thi Thu Ha Nguyen⁴, Nur Mohammad Monsur Hassan⁵, Akira Sasaki¹

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan.
² Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan.
³ Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan.
⁴ Department of Oral Rehabilitation Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan.
⁵ School of Dentistry and Health Sciences, Charles Sturt University, Sydney, Orange NSW, Australia.

PMID: 29328370
DOI: 10.3892/ijo.2018.4242

Abstract

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically where one of the mechanisms responsible for the invasion into facial bones occurs via the activation of osteoclasts. Copper has been demonstrated to play a key role in skeletal remodeling. However, the role of copper in cancer-associated bone destruction is thus far unknown. Lysyl oxidase (LOX) is a copper-dependent enzyme that promotes osteoclastogenesis. In the present study, we investigated the effects of copper on HNSCC with bone invasion by the copper chelator, ammonium tetrathiomolybdate (TM) in vitro and in vivo. We demonstrate that TM blocks the proliferation of HNSCC cells, inhibits LOX activation and decreases the expression of the receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts and osteocytes, subsequently suppressing bone destruction. These findings suggest that copper is a potential target for the treatment of HNSCCs associated with bone destruction.

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
Antineoplastic Agents, Immunological / therapeutic use
Bone Neoplasms / drug therapy*
Bone Neoplasms / pathology
Bone Neoplasms / secondary
Bone Resorption / drug therapy*
Bone Resorption / pathology
Carcinoma, Squamous Cell / drug therapy*
Carcinoma, Squamous Cell / pathology
Cetuximab / pharmacology
Cetuximab / therapeutic use
Chelating Agents / pharmacology*
Chelating Agents / therapeutic use
Copper / metabolism*
Drug Synergism
Female
Head and Neck Neoplasms / drug therapy*
Head and Neck Neoplasms / pathology
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Molybdenum / pharmacology
Molybdenum / therapeutic use
Neoplasm Invasiveness / pathology
Osteoclasts / drug effects*
Osteoclasts / physiology
Protein-Lysine 6-Oxidase / metabolism
RANK Ligand / metabolism
Squamous Cell Carcinoma of Head and Neck
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
Chelating Agents
RANK Ligand
TNFSF11 protein, human
Copper
Molybdenum
tetrathiomolybdate
Protein-Lysine 6-Oxidase
Cetuximab