31P and 1H MRS of DB-1 melanoma xenografts: Lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan

Kavindra Nath, David S. Nelson, Andrew M. Ho, Seung Cheol Lee, Moses M. Darpolor, Stephen Pickup, Rong Zhou, Daniel F. Heitjan, Dennis B. Leeper, Jerry D. Glickson

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In vivo 31P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pHi) from 6.90±0.05 to 6.33±0.10 (p<0.001), a slight decrease in extracellular pH (pHe) from 7.00±0.04 to 6.80±0.07 (p>0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8±5.7% (p<0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2±0.1 pH units (p>0.05) at 20min post-LND, with no significant change in pHe and a small transient decrease in bioenergetics (32.9±10.6%, p>0.05) at 40min post-LND. No changes in pHi or adenosine triphosphate/inorganic phosphate were detected in the brain (pHi, bioenergetics; p>0.1) or skeletal muscle (pHi, pHe, bioenergetics; p>0.1) for at least 120min post-LND. Steady-state tumor lactate monitored by 1H MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three-fold (p=0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5mg/kg intravenously), producing a growth delay of 19.9±2.0days (tumor doubling time, 6.15±0.31days; log10 cell kill, 0.975±0.110; cell kill, 89.4±2.2%) compared with LND alone of 1.1±0.1days and LPAM alone of 4.0±0.0days. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalNMR in biomedicine
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Lonidamine
  • Melanoma
  • Melphalan
  • Monocarboxylic acid transporter
  • P MRS
  • Tumor acidification

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

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  • Cite this

    Nath, K., Nelson, D. S., Ho, A. M., Lee, S. C., Darpolor, M. M., Pickup, S., Zhou, R., Heitjan, D. F., Leeper, D. B., & Glickson, J. D. (2013). 31P and 1H MRS of DB-1 melanoma xenografts: Lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan. NMR in biomedicine, 26(1), 98-105. https://doi.org/10.1002/nbm.2824