Selective acidification and de-energization of cancers via inhibition of monocarboxylate transporters (MCTs), mitochondrial pyruvate carrier (MPC), and Electron Transport Chain (ETC).
Development of a safe and reproducible method to selectively acidify and de-energize the human cancer xenografts. Specifically, we seek to employ the natural tendency of cancers to convert glucose to lactate as a method for selective intracellular acidification, which is known to potentiate tumor response to chemotherapy, radiation therapy, hyperthermia, and photodynamic therapy. In vivo 31P and 1H Magnetic Resonance Spectroscopy demonstrated that human cancer xenografts such as melanoma, breast, prostate and ovarian in immunosuppressed mice treated with MCT, MPC and ETC inhibitor, lonidamine, exhibit a sustained and tumor-selective decrease in pH, bioenergetics and increase in lactate and subsequent sensitization to nitrogen mustards, doxorubicin and radiation therapy.
Mouse Xenograft development, tumor cells studies, drug delivery, metabolomics, and tumor micro-environment modulation.
Surface coil development for mouse xenografts.
1H, 31P, 13C Spectroscopy, T1, T2, Diffusion weighted and Dynamic Contrast Enhanced (DCE) MRI of mouse xenografts.
Diffusion tensor imaging and proton magnetic resonance spectroscopy of patients with various intracranial mass lesions.
Measurement of test-retest reproducibility of SUV (Subsidized Uptake Value) on PET under clinical practice conditions in cancer patients.
Nath K, Guo L, Nancolas B, Nelson DS, Shestov AA, Lee SC, Roman J, Zhou R, Leeper DB, Halestrap AP, Blair IA, Glickson JD.: Mechanism of antineoplastic activity of lonidamine. BBA Reviews on Cancer 1866(2): 151-162, 2016.
Nath K, Nelson DS, Putt ME, Leeper DB, Garman B, Nathanson KL, Glickson JD: 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(6), 2016.
Kumar D, Gupta A, Nath K: NMR-based metabolomics of prostate cancer: a protagonist in clinical diagnostics. Expert Rev Mol Diagn. 16(6): 651-61, 2016.
Alexander A Shestov, Seung-Cheol Lee, Kavindra Nath, Lili Guo, David Samuel Nelson, Jeffrey C Roman, Dennis B Leeper, Mariusz A Wasik, Ian A Blair, Jerry David Glickson: 13C MRS and LC-MS Flux Analysis of Tumor Intermediary Metabolism. Front. Oncol. 6(135), 2016.
Nancolas B, Guo L, Zhou R, Nath K, Nelson DS, Leeper DB, Blair IA, Glickson JD, Halestrap AP.: The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters. Biochem J. 473(7): 929-36, 2016.
Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, Glickson JD, Blair IA. : Inhibition of mitochondrial complex II by the anti-cancer agent lonidamine. J Biol Chem. 291(1): 42-57, 2016.
De Brosse K, Nanga R, Bagga P, Nath K, Haris M, Marincola F, Schnall M, Hariharan H, Reddy R: Lactate Chemical Exchange Saturation Transfer (LATEST) Imaging in vivo: A Biomarker for LDH Activity. Sci Rep. 6: 19517, 2016.
Nath Kavindra, Nelson David S, Heitjan Daniel F, Zhou Rong, Leeper Dennis B, Glickson Jerry D. : Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. NMR in Biomedicine 28(3): 395-403, 2015.
Nath Kavindra, Nelson David S, Heitjan Daniel F, Leeper Dennis B, Zhou Rong, Glickson Jerry D: Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR in Biomedicine 28(3): 281-290, 2015.
Ting Liu, Kavindra Nath, Weixia Liu, Rong Zhou, I-Wei Chen: A study of the relationship of metabolic MR parameters to estrogen dependence in breast cancer xenografts. NMR in Biomedicine 28(9): 1087-96, 2015.
back to top
Last updated: 09/07/2016
The Trustees of the University of Pennsylvania