Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan
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 whethe...
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crwiley:10.1002/nbm.3260 2024-06-23T07:52:04+00:00 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. National Institutes of Health 2015 http://dx.doi.org/10.1002/nbm.3260 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fnbm.3260 http://onlinelibrary.wiley.com/wol1/doi/10.1002/nbm.3260/fullpdf en eng Wiley http://onlinelibrary.wiley.com/termsAndConditions#vor NMR in Biomedicine volume 28, issue 3, page 395-403 ISSN 0952-3480 1099-1492 journal-article 2015 crwiley https://doi.org/10.1002/nbm.3260 2024-05-31T08:11:56Z 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 (pH i ), extracellular pH (pH e ) 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 p K a 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. Copyright © 2015 John Wiley & Sons, Ltd. Article in Journal/Newspaper Carbonic acid Wiley Online Library NMR in Biomedicine 28 3 395 403 |
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English |
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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 (pH i ), extracellular pH (pH e ) 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 p K a 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. Copyright © 2015 John Wiley & Sons, Ltd. |
author2 |
National Institutes of Health |
format |
Article in Journal/Newspaper |
author |
Nath, Kavindra Nelson, David S. Heitjan, Daniel F. Zhou, Rong Leeper, Dennis B. Glickson, Jerry D. |
spellingShingle |
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 |
author_facet |
Nath, Kavindra Nelson, David S. Heitjan, Daniel F. Zhou, Rong Leeper, Dennis B. Glickson, Jerry D. |
author_sort |
Nath, Kavindra |
title |
Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
title_short |
Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
title_full |
Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
title_fullStr |
Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
title_full_unstemmed |
Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
title_sort |
effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan |
publisher |
Wiley |
publishDate |
2015 |
url |
http://dx.doi.org/10.1002/nbm.3260 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fnbm.3260 http://onlinelibrary.wiley.com/wol1/doi/10.1002/nbm.3260/fullpdf |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_source |
NMR in Biomedicine volume 28, issue 3, page 395-403 ISSN 0952-3480 1099-1492 |
op_rights |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
op_doi |
https://doi.org/10.1002/nbm.3260 |
container_title |
NMR in Biomedicine |
container_volume |
28 |
container_issue |
3 |
container_start_page |
395 |
op_container_end_page |
403 |
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1802643265400340480 |