Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin

Abstract Lonidamine (LND), a metabolic modulator, sensitizes DB-1 human melanoma to doxorubicin (DOX) chemotherapy by acidifying and de-energizing the tumor. This report compares the effects of LND on two human melanoma lines, DB-1 and WM983B, which exhibit different metabolic properties. Using liqu...

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Autores principales:	Kavindra Nath, Jeffrey Roman, David S. Nelson, Lili Guo, Seung-Cheol Lee, Stepan Orlovskiy, Kevin Muriuki, Daniel F. Heitjan, Stephen Pickup, Dennis B. Leeper, Ian A. Blair, Mary E. Putt, Jerry D. Glickson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Lonidamine (LND) Growth Delay Seahorse Tumor Lactate Levels Extracellular Acidification Rate (ECAR) Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0e896a59367143cd9eaf61fe48cf3d20
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spelling	oai:doaj.org-article:0e896a59367143cd9eaf61fe48cf3d202021-12-02T15:08:58ZEffect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin10.1038/s41598-018-33019-42045-2322https://doaj.org/article/0e896a59367143cd9eaf61fe48cf3d202018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33019-4https://doaj.org/toc/2045-2322Abstract Lonidamine (LND), a metabolic modulator, sensitizes DB-1 human melanoma to doxorubicin (DOX) chemotherapy by acidifying and de-energizing the tumor. This report compares the effects of LND on two human melanoma lines, DB-1 and WM983B, which exhibit different metabolic properties. Using liquid chromatography mass spectrometry and Seahorse analysis, we show that DB-1 was more glycolytic than WM983B in vitro. 31P magnetic resonance spectroscopy (MRS) indicates that LND (100 mg/kg, i.p.) induces similar selective acidification and de-energization of WM983B xenografts in immunosuppressed mice. Over three hours, intracellular pH (pHi) of WM983B decreased from 6.91 ± 0.03 to 6.59 ± 0.10 (p = 0.03), whereas extracellular pH (pHe) of this tumor changed from 7.03 ± 0.05 to 6.89 ± 0.06 (p = 0.19). A decline in bioenergetics (β-NTP/Pi) of 55 ± 5.0% (p = 0.03) accompanied the decline in pHi of WM983B. Using 1H MRS with a selective multiquantum pulse sequence and Hadamard localization, we show that LND induced a significant increase in tumor lactate levels (p < 0.01). LND pre-treatment followed by DOX (10 mg/kg, i.v.) produced a growth delay of 13.7 days in WM983B (p < 0.01 versus control), a growth delay significantly smaller than the 25.4 days that occurred with DB-1 (p = 0.03 versus WM983B). Differences in relative levels of glycolysis may produce differential therapeutic responses of DB-1 and WM983B melanomas.Kavindra NathJeffrey RomanDavid S. NelsonLili GuoSeung-Cheol LeeStepan OrlovskiyKevin MuriukiDaniel F. HeitjanStephen PickupDennis B. LeeperIan A. BlairMary E. PuttJerry D. GlicksonNature PortfolioarticleLonidamine (LND)Growth DelaySeahorseTumor Lactate LevelsExtracellular Acidification Rate (ECAR)MedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lonidamine (LND) Growth Delay Seahorse Tumor Lactate Levels Extracellular Acidification Rate (ECAR) Medicine R Science Q
spellingShingle	Lonidamine (LND) Growth Delay Seahorse Tumor Lactate Levels Extracellular Acidification Rate (ECAR) Medicine R Science Q Kavindra Nath Jeffrey Roman David S. Nelson Lili Guo Seung-Cheol Lee Stepan Orlovskiy Kevin Muriuki Daniel F. Heitjan Stephen Pickup Dennis B. Leeper Ian A. Blair Mary E. Putt Jerry D. Glickson Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
description	Abstract Lonidamine (LND), a metabolic modulator, sensitizes DB-1 human melanoma to doxorubicin (DOX) chemotherapy by acidifying and de-energizing the tumor. This report compares the effects of LND on two human melanoma lines, DB-1 and WM983B, which exhibit different metabolic properties. Using liquid chromatography mass spectrometry and Seahorse analysis, we show that DB-1 was more glycolytic than WM983B in vitro. 31P magnetic resonance spectroscopy (MRS) indicates that LND (100 mg/kg, i.p.) induces similar selective acidification and de-energization of WM983B xenografts in immunosuppressed mice. Over three hours, intracellular pH (pHi) of WM983B decreased from 6.91 ± 0.03 to 6.59 ± 0.10 (p = 0.03), whereas extracellular pH (pHe) of this tumor changed from 7.03 ± 0.05 to 6.89 ± 0.06 (p = 0.19). A decline in bioenergetics (β-NTP/Pi) of 55 ± 5.0% (p = 0.03) accompanied the decline in pHi of WM983B. Using 1H MRS with a selective multiquantum pulse sequence and Hadamard localization, we show that LND induced a significant increase in tumor lactate levels (p < 0.01). LND pre-treatment followed by DOX (10 mg/kg, i.v.) produced a growth delay of 13.7 days in WM983B (p < 0.01 versus control), a growth delay significantly smaller than the 25.4 days that occurred with DB-1 (p = 0.03 versus WM983B). Differences in relative levels of glycolysis may produce differential therapeutic responses of DB-1 and WM983B melanomas.
format	article
author	Kavindra Nath Jeffrey Roman David S. Nelson Lili Guo Seung-Cheol Lee Stepan Orlovskiy Kevin Muriuki Daniel F. Heitjan Stephen Pickup Dennis B. Leeper Ian A. Blair Mary E. Putt Jerry D. Glickson
author_facet	Kavindra Nath Jeffrey Roman David S. Nelson Lili Guo Seung-Cheol Lee Stepan Orlovskiy Kevin Muriuki Daniel F. Heitjan Stephen Pickup Dennis B. Leeper Ian A. Blair Mary E. Putt Jerry D. Glickson
author_sort	Kavindra Nath
title	Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
title_short	Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
title_full	Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
title_fullStr	Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
title_full_unstemmed	Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin
title_sort	effect of differences in metabolic activity of melanoma models on response to lonidamine plus doxorubicin
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/0e896a59367143cd9eaf61fe48cf3d20
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Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin

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