tetrathiomolybdate and Lung-Neoplasms

Since its domestication more than 10,000 years ago, the dog has been the animal that most intimately shares our work and homelife. Interestingly, the dog also shares many of our diseases including cancer such as osteosarcoma. Like the human, osteosarcoma is the most common bone malignancy of the dog and death from pulmonary metastasis is the most common outcome. The incidence of this spontaneous bone neoplasm occurs ten times more frequently that it does so in children with about 8,000-10,000 cases estimated to occur in dogs in the USA. Because there is no "standard of care" in veterinary medicine, the dog can also serve us by being a model for this disease in children. Although the most common therapy for the dog with osteosarcoma is amputation followed by chemotherapy, not all owners choose this route. Consequently, novel therapeutic interventions can be attempted in the dog with or without chemotherapy that could not be done in humans with osteosarcoma due to ethical concerns. This chapter will focus on the novel therapies in the dog that have been reported or are in veterinary clinical trials at the author's institution. It is hoped that collaboration between veterinary oncologists and pediatric oncologists will lead to the development of novel therapies for (micro- or macro-) metastatic osteosarcoma that improve survival and might ultimately lead to a cure in both species.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Aerosols; Animals; Antineoplastic Agents; Bone Neoplasms; Child; Deoxycytidine; Dog Diseases; Dogs; Gemcitabine; Humans; Interleukin-2; Lung Neoplasms; Molybdenum; Osteosarcoma; Phosphatidylethanolamines; Signal Transduction

Although anti- angiogenesis strategies have generated much enthusiasm for therapeutic applications, it is still unknown whether they would be feasible for prevention. The possibility of interfering very early in tumor progression by modulating the cancer angiogenic switch is appealing. In this chapter, we review progress with in vitro and in vivo models that show that anti-angiogenic interventions may be amenable to long- term chemopreventive measures. In particular, some approaches that are nearly ready for major applications are anti-oxidant nutraceuticals and copper deficiency. We use these strategies as paradigms of how to make progress in this difficult but important area of translational research.

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Antioxidants; Breast Neoplasms; Carotenoids; Cell Transformation, Neoplastic; Chelating Agents; Copper; Dietary Supplements; Female; Flavonoids; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Molybdenum; Neoplasms; Neovascularization, Pathologic; NF-kappa B; Phenols; Polyphenols; Prostatic Neoplasms; Reactive Oxygen Species

Bone marrow-derived progenitor cells, including VEGFR2. Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.. Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).. Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. ©2016 AACR.

Topics: Adenocarcinoma; Amino Acid Oxidoreductases; Animals; Breast Neoplasms; Cell Line, Tumor; Ceruloplasmin; Chelating Agents; Copper; Disease Progression; Disease-Free Survival; Endothelial Progenitor Cells; Female; Follow-Up Studies; Humans; Lung Neoplasms; Mice, SCID; Molybdenum; Neoplasm Proteins; Neovascularization, Pathologic; Neutropenia; Risk; Triple Negative Breast Neoplasms; Tumor Microenvironment; Xenograft Model Antitumor Assays

Cisplatin-based chemotherapy is the standard treatment for non-small cell lung cancer (NSCLC). However, cisplatin resistance is a major obstacle to successful therapeutic efficacy. Novel therapeutic strategies are urgently needed to reverse chemotherapy resistance and improve prognosis. In the present study, we aimed to investigate whether copper chelator Tetrathiomolybdate (TM) can enhance the anticancer effect of cisplatin, and elucidate the underlying mechanisms.. Cell viability, wounding healing, and colony formation assays were performed on H1299 and A549 cells. The combination indices (CI) were determined by the Chou-Talalay method. Flow cytometry was used to detect cell apoptosis and ROS generation. GSH levels were measured in a microplate reader. RNA-seq and bioinformatics analyses were used to analyze the differentially expressed genes (DEGs) and enriched biology processes. The concentrations of Pt and Cu were determined by ICP-MS. Animal xenograft tumor model was established to evaluate the synergistic anticancer effect of TM and cisplatin.. Combination treatment with TM and cisplatin decreased cell viability and migration of H1299 and A549 cells compared with cisplatin alone. Mechanistically, combination treatment could significantly increase ROS and reduce GSH content, leading to a notable increase in DNA-bound Pt and cell apoptosis. Moreover, in animal xenograft tumor model, TM enhanced cisplatin-elicited antitumor effect, but did not increase cisplatin-induced side effects.. Our study suggests that TM may be a promising chemotherapeutic sensitizer for non-small cell lung cancer.

Topics: A549 Cells; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Molybdenum; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Approximately 85% of lung cancers are non–small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224–dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H(2)O(2)) levels. We found that ATN-224–induced cell death was mediated through H(2)O(2)-dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Hydrogen Peroxide; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molybdenum; Myeloid Cell Leukemia Sequence 1 Protein; Sulfonamides; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Burden; Tumor Suppressor Protein p53

Angiogenesis is well recognized as an essential process that influences not only the growth of head and neck squamous cell carcinoma (HNSCC) but also promotes its invasive and metastatic behavior. The critical role of copper in multiple facets of angiogenesis makes it an important therapeutic target. Tetrathiomolybdate is a potent copper chelator, which has shown remarkable ability to suppress angiogenesis. Although this may involve multiple mechanisms, the effects on vascular endothelial growth factor (VEGF) are pivotal. In previous work, tetrathiomolybdate suppressed production of several proangiogenic cytokines by HNSCC cell lines. Given these results, we hypothesized that tetrathiomolybdate would impair tumor growth and metastasis by HNSCC. To test this concept, we evaluated the effects of long-term tetrathiomolybdate treatment on the growth and metastatic progression of HNSCC using a xenograft animal model. The results showed that tetrathiomolybdate treatment is able to maintain effective inhibition of angiogenesis. There was a significant reduction in the tumor size and vascularity with evident gross necrosis in the tetrathiomolybdate-treated animals. These effects were highly correlated with suppression of human VEGF expressed in the developing tumors as well as the mouse VEGF levels detected in the plasma. Moreover, tetrathiomolybdate treatment drastically suppressed the development of lung metastases. Taken together, these results show that tetrathiomolybdate can act long-term as a suppressor of vascularity and inhibit the growth of metastasis in this model of HNSCC.

Topics: Adenosine Triphosphatases; Angiogenesis Inhibitors; Animals; Carcinoma, Squamous Cell; Cell Movement; Ceruloplasmin; Disease Models, Animal; Head and Neck Neoplasms; Humans; Lung Neoplasms; Mice; Mice, Nude; Molybdenum; Necrosis; Neovascularization, Pathologic; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Tetrathiomolybdate (TM) is an anticopper drug under development for treating Wilson's disease. Its mechanism of action involves forming a tight tripartite complex in the blood with serum albumin and available copper. When available copper levels are lowered in animals with TM, strong antiangiogenic and antitumor effects are observed. Similarly, TM has excellent efficacy in animal models of fibrotic, inflammatory, and autoimmune diseases, and it protects against heart damage from doxorubicin (DXR) and liver damage from acetaminophen, carbon tetrachloride, and concanavalin A. Tetrathiotungstate (TT) also forms a similar tripartite complex in the blood and has similar effects to TM on copper. In this article, whether TT had similar antitumor effects, and similar effects in protecting the heart against DXR toxicity, as TM was evaluated. It was found that the 2 drugs were comparable in their effects when doses were used that lowered copper availability to the same extent.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Biomarkers; Carcinoma, Lewis Lung; Ceruloplasmin; Copper; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Doxorubicin; Heart Diseases; Inflammation; L-Lactate Dehydrogenase; Lung Neoplasms; Mice; Mice, Inbred C57BL; Molybdenum; Troponin I; Tungsten Compounds

Tetrathiomolybdate (TM), a specific copper chelator, has been shown to be a potent antiangiogenic and antimetastatic compound possibly through suppression of the NFkappaB signaling cascade. To further delineate the molecular mechanism of the anticancer effect of TM, we investigated whether TM has antineoplastic activity in the setting of genetic NFkappaB inhibition. In this study, SUM149 inflammatory breast carcinoma cells were transfected with a dominant-negative IkappaBalpha (S32AS36A) expression vector. Similar to TM-treated SUM149 cells, SUM149-IkappaBalphaMut clones secreted lower amounts of proangiogenic mediators, vascular endothelial growth factor, interleukin-1alpha, and interleukin-8 and exhibited a less invasive and motile phenotype. The reduction in the angiogenic and metastatic potential of SUM149-IkappaBalphaMut clones was not further affected by TM in vitro. SUM149-IkappaBalphaMut xenografts grew substantially slower and had less lung metastasis than SUM149 and SUM149-empty vector xenografts. The growth and metastatic potential of SUM149 and SUM149-empty tumors was significantly inhibited with systemic TM treatment, whereas TM had no further antitumor effect on the SUM149-IkappaBalphaMut tumors. Additionally, nuclear proteins isolated from TM-treated SUM149 tumors had lower NFkappaB binding activity, while AP1 and SP1 binding activities were unchanged. Taken together, these results strongly support that suppression of NFkappaB is the major mechanism used by TM to inhibit angiogenesis and metastasis.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Cell Division; Cell Line, Tumor; Female; I-kappa B Proteins; Lung Neoplasms; Mice; Molybdenum; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; NF-KappaB Inhibitor alpha; Transcription, Genetic; Transfection; Xenograft Model Antitumor Assays