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 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.

The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

“…Thus, the pH gradient of tumor was reversed so that free basic DOX (pKa ~8.5) would be more readily captured in the acidified tumor cells (cation trapping) [ 54 ]; (2) for another, similar to TMZ and NM, LND-mediated tumor de-energization inhibits energy-dependent MDR efflux pumps, resulting in more DOX retained in tumor cells. In 2018, Nath et al reported the combined effect of LND plus DOX against two different human melanoma cell lines (DB-1 and WM983B) [ 56 ]. It was found that WM983B melanoma was less glycolytic than DB-1, however, intracellular acidification and de-energization were also induced after exposure to LND in immunosuppressed mice WM983B xenografts.…”

“…In addition to enhanced glycolysis, the increased pentose phosphate pathway (PPP) flux, the high rates of glutaminolysis, and the synthesis of fatty acids (FAs) are also the malignant metabolic phenotypes of cancer cells [ 58 , 84 , 85 ]. When glycolysis is inhibited, glucose metabolism is impaired; however, tumor cells can survive by utilizing the glutaminolysis as a complementary surviving pathway, and vice versa [ 56 , 58 ]. Therefore, it is considered to kill cancer cells through the combined inhibition of malignant metabolic pathways.…”

“…As mentioned above [ 56 ], we have discussed the sensitivity of two different melanoma models to the combination of LND plus DOX. Compared to DB-1 melanoma xenograft, WM983B melanoma xenograft responded less to DOX [ 56 ].…”

“…As mentioned above [ 56 ], we have discussed the sensitivity of two different melanoma models to the combination of LND plus DOX. Compared to DB-1 melanoma xenograft, WM983B melanoma xenograft responded less to DOX [ 56 ]. Of note, after LND treatment, WM983B melanoma xenografts upregulated glutaminolysis to compensate the energy deprivation caused by LND-mediated MPC inhibition [ 56 ].…”

“…Compared to DB-1 melanoma xenograft, WM983B melanoma xenograft responded less to DOX [ 56 ]. Of note, after LND treatment, WM983B melanoma xenografts upregulated glutaminolysis to compensate the energy deprivation caused by LND-mediated MPC inhibition [ 56 ]. The high rate of glutaminolysis provides a readily available source of carbon backbone and nitrogen that promotes tumor growth [ 86 ].…”