Melanoma is the most virulent of all the skin cancers. While often cured by early surgical excision, there is no generally effective method for treating disseminated disease. We propose to sensitize melanoma to cisplatin and cyclophosphamide utilizing a method for selective acidification of melanomas that we have recently developed. The basic strategy is to induce systemic hyperglycemia by i.v. infusion of glucose to maintain a vascular glucose concentration of 26?1 mM (465 mg/dL) to drive lactate production. To maximize tumor lactate production meta-iodobenzylguanidine (MIBG), an inhibitor of site-1 of the on of melanomas that we have recently developed. The basic strategy is to induce systemic hyperglycemia by i.v. infusion of glucose to maintain a vascular glucose concentration of 26?1 mM (465 mg/dL) to drive lactate production. To maximize tumor lactate production meta-iodobenzylguanidine (MIBG), an inhibitor of site-1 of the respiratory electron transport chain, is administered. Lactate is then trapped inside the tumor cells by administration of an inhibitor of the monocarboxylic aective metabolic acidification procedure to clinical translation by eliminating CNCn, which is not FDA approved, or replacing CNCn and with lonidamine, an agent that inhibits the MCT and also blocks oxidative phosphorylation by preventing pyruvate transfer into mitochondria. Lonidamine is widely used in the clinic in Europe, and the FDA has granted INDs for its use in the USA. Once the optimum selective acidification procedure is perfected on the DB1 tumor, we will determine if this method enhances the efficacy of cisplatin and cyclophosphamide against xenografts of this tumor in nude mice.
Aim 2 will utilize histopathology, serum enzyme assays and a variety of functional tests utilizing our expertise in MRS and MRI as well as NIR optical redox scanning to examine the toxicity of these procedures to various critical normal tissues.
NMR of Melanoma Acidification, Bioenergetics, Metabolism and Therapeutic Response Project Narrative Melanoma, the most virulent form of skin cancer, is not responsive to chemotherapy. This project proposes to develop a method to sensitize melanomas to chemotherapy by selectively acidifying the cancer cells while minimally affecting normal cells. The method takes advantage of the fact that cancer cells prefer glucose as their primary source of energy and convert it to lactic acid.
|Nath, Kavindra; Nelson, David S; Roman, Jeffrey et al. (2017) Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide. Anticancer Res 37:3413-3421|
|Nancolas, Bethany; Guo, Lili; Zhou, Rong et al. (2016) The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters. Biochem J 473:929-36|
|Shestov, Alexander A; Mancuso, Anthony; Lee, Seung-Cheol et al. (2016) Bonded Cumomer Analysis of Human Melanoma Metabolism Monitored by 13C NMR Spectroscopy of Perfused Tumor Cells. J Biol Chem 291:5157-71|
|Nath, Kavindra; Nelson, David S; Putt, Mary E et al. (2016) Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice. PLoS One 11:e0157125|
|Shestov, Alexander A; Lee, Seung-Cheol; Nath, Kavindra et al. (2016) (13)C MRS and LC-MS Flux Analysis of Tumor Intermediary Metabolism. Front Oncol 6:135|
|Nath, Kavindra; Guo, Lili; Nancolas, Bethany et al. (2016) Mechanism of antineoplastic activity of lonidamine. Biochim Biophys Acta 1866:151-162|
|Guo, Lili; Worth, Andrew J; Mesaros, Clementina et al. (2016) Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. Rapid Commun Mass Spectrom 30:1835-45|
|Guo, Lili; Shestov, Alexander A; Worth, Andrew J et al. (2016) Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. J Biol Chem 291:42-57|
|Nath, Kavindra; Nelson, David S; Heitjan, Daniel F et al. (2015) Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed 28:281-90|
|Nath, Kavindra; Nelson, David S; Heitjan, Daniel F et al. (2015) Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. NMR Biomed 28:395-403|
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