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

• Published in: NMR in Biomedicine
• Main Authors: Nath, Kavindra, Nelson, David S., Heitjan, Daniel F., Zhou, Rong, Leeper, Dennis B., Glickson, Jerry D.
• Format: Text
• Language: English
• Published: 2015
• Subjects: Article; Carbonic acid
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361035/; http://www.ncbi.nlm.nih.gov/pubmed/25702942; https://doi.org/10.1002/nbm.3260

We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for selective intracellular acidification of cancer cells and for potentiating the activity of N-mustard antineoplastic agents. We performed this study to evaluate whether induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; i.p.) on inducing 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 (βNTP/Pi) were reduced by 0.7 units (p<0.001), 0.3 units (p>0.05) and 51.4% (p<0.05), respectively. Therapeutic response to LPAM (7.5 mg/kg; i.v.) + LND (100 mg/kg; i.p.) was reduced by about a factor of 3 under hyperglycemic conditions compared to normoglycemia, producing a growth delay of 7.76 d (tumor doubling time = 5.31 d, cell kill = 64%) compared to LND alone of 1.70 d and LPAM alone of 0.29 d. Under normoglycemic conditions LND plus LPAM produced a growth delay of 17.75 d, corresponding to a cell kill of 90 % at the same doses 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 ~6 (p<0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor most likely because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that addition of glucose during treatment with LND diminishes the activity of this agent.