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

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

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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.

Original languageEnglish (US)
Article number14654
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Nath, K., Roman, J., Nelson, D. S., Guo, L., Lee, S. C., Orlovskiy, S., ... Glickson, J. D. (2018). Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin. Scientific Reports, 8(1), [14654]. https://doi.org/10.1038/s41598-018-33019-4