tetrathiomolybdate and Squamous-Cell-Carcinoma-of-Head-and-Neck

Platinum‑based antitumor agents have been widely used to treat head and neck squamous cell carcinoma (HNSCC) and numerous other malignancies. Cisplatin is the most frequently used platinum‑based antitumor agent, however drug resistance and numerous undesirable side effects limit its clinical efficacy for cancer patients. Cancer cells discharge cisplatin into the extracellular space via copper transporters such as ATPase copper transporting beta (ATP7B) in order to escape from cisplatin‑induced cell death. In the present study, it was demonstrated for the first time that the copper chelator ammonium tetrathiomolybdate (TM) has several promising effects on cisplatin and HNSCC. First, TM suppressed the ATP7B expression in HNSCC cell lines in vitro, thereby enhancing the accumulation and apoptotic effect of cisplatin in the cancer cells. Next, it was revealed that TM enhanced the antitumor effect of cisplatin in HNSCC cell tumor progression in a mouse model of bone invasion, which is important since HNSCC cells frequently invade to facial bone. Finally, it was demonstrated that TM was able to overcome the cisplatin resistance of a human cancer cell line, A431, via ATP7B depression in vitro.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cisplatin; Copper-Transporting ATPases; Drug Resistance, Neoplasm; Drug Synergism; Head and Neck Neoplasms; Humans; Male; Mice; Molybdenum; Squamous Cell Carcinoma of Head and Neck; Tissue Array Analysis; Xenograft Model Antitumor Assays

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.

Topics: Animals; Antineoplastic Agents, Immunological; Bone Neoplasms; Bone Resorption; Carcinoma, Squamous Cell; Cetuximab; Chelating Agents; Copper; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Molybdenum; Neoplasm Invasiveness; Osteoclasts; Protein-Lysine 6-Oxidase; RANK Ligand; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Xenograft Model Antitumor Assays