Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan

Kavindra Nath, David S. Nelson, Daniel F. Heitjan, Rong Zhou, Dennis B. Leeper, Jerry D. Glickson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen-mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi), extracellular pH (pHe) and bioenergetics (β-nucleoside triphosphate to inorganic phosphate ratio, β-NTP/Pi) were reduced by 0.7 units (p < 0.001), 0.3 units (p > 0.05) and 51.4% (p < 0.05), respectively. The therapeutic response to LPAM (7.5 mg/kg; intravenously) + LND (100 mg/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (p < 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent.

Original languageEnglish (US)
Pages (from-to)395-403
Number of pages9
JournalNMR in Biomedicine
Volume28
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Melphalan
Acidification
Heterografts
Hyperglycemia
Tumors
Melanoma
Neoplasms
Lactic Acid
Energy Metabolism
Carbonic Acid
Cells
Glucose
Mechlorethamine
Nucleosides
Carbon Dioxide
Antineoplastic Agents
Growth
lonidamine
Adenosine Triphosphate
Phosphates

Keywords

  • Lonidamine
  • Melphalan
  • Monocarboxylate transport inhibitor
  • MRS
  • Tumor acidification
  • Tumor de-energization

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

Cite this

Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. / Nath, Kavindra; Nelson, David S.; Heitjan, Daniel F.; Zhou, Rong; Leeper, Dennis B.; Glickson, Jerry D.

In: NMR in Biomedicine, Vol. 28, No. 3, 01.01.2015, p. 395-403.

Research output: Contribution to journalArticle

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. In: NMR in Biomedicine. 2015 ; Vol. 28, No. 3. pp. 395-403.
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