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

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

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

Authors:
- Ayaka Morisawa
- Tatsuo Okui
- Tsuyoshi Shimo
- Soichiro Ibaragi
- Yuka Okusha
- Mitsuaki Ono
- Thi Thu Ha Nguyen
- Nur Mohammad Monsur Hassan
- Akira Sasaki
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Affiliations: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan, Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan, Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan, Department of Oral Rehabilitation Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan, School of Dentistry and Health Sciences, Charles Sturt University, Sydney, Orange NSW, Australia
Published online on: January 10, 2018 https://doi.org/10.3892/ijo.2018.4242
Pages: 989-999

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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.

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