³¹P and¹H MRS of DB‐1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan

Abstract

In vivo 31P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg, i.p.) exhibit a decrease in intracellular pH (pHi) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pHe) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05), and a monotonic decline in bioenergetics (NTP/Pi) by 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3 hr following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND with no significant change in pHe and a small transient decrease in bioenergetics, 32.9 ± 10.6 % (p > 0.05), at 40 min post-LND. No changes in pHi or ATP/Pi were detected in the brain (pHi, bioenergetics; p > 0.1) or skeletal muscle (pHi, pHe, bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by 1H MRS with a selective multiquantum pulse sequence with Hadamard localization increased ~3-fold (p = 0.009). Treatment with LND increased systemic melanoma response to melphalan (LPAM; 7.5 mg/kg, i.v.) producing a growth delay of 19.9 ± 2.0 d (tumor doubling time = 6.15 ± 0.31d, log10 cell-kill = 0.975 ± 0.110, cell-kill = 89.4 ± 2.2%) compared to LND alone of 1.1 ± 0.1 d and LPAM alone of 4.0 ± 0.0 d. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH-dependent therapeutics such as chemotherapy with alkylating agents or hyperthermia.

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide

“…Our recent 31 that this agent inhibited glycolytic activity at hexokinase II (21), we observed that the level of lactic acid in the tumor increased 3-fold over 3 h (11,13,14). Tumor acidification and de-energization were detected in a variety of tumors grown as xenografts in mice, including various melanomas, both triplypositive and triply-negative breast tumors, ovarian cancer and prostate cancer (12).…”

“…We have presented 31 P and 1 H magnetic resonance spectroscopy (MRS) results (Figure 4) in the current study with representative phosphorus spectra to delineate the time window for intracellular acidification, bioenergetic decline and lactate production in DB-1 melanoma xenografts following LND administration at time zero (11,14). In the current study, TMZ was injected at t=40 min after LND administration.…”

“…Tumor acidification and de-energization were detected in a variety of tumors grown as xenografts in mice, including various melanomas, both triplypositive and triply-negative breast tumors, ovarian cancer and prostate cancer (12). At this dose level, LND produced no effect on normal skeletal muscle or brain and had only a small transient effect on liver metabolism (13,14). The Warburg effect discovered by Otto Warburg states that most tumors exhibit high level of aerobic glycolysis and has been exploited for the detection and treatment of cancer (22).…”

“…The Warburg effect discovered by Otto Warburg states that most tumors exhibit high level of aerobic glycolysis and has been exploited for the detection and treatment of cancer (22). We wanted to exploit this natural preference of tumors for glycolytic metabolism as a method to selectively induce intracellular acidification of the tumor by accumulation of lactic acid even under aerobic conditions and use this selective tumor acidification and de-energization to enhance tumor response to chemotherapeutic agents, such as N-mustards and doxorubicin (11)(12)(13)(14)(15). Others had shown that LND sensitizes tumors to hyperthermia (23)(24)(25)(26), radiotherapy (27,28) and photodynamic therapy (29) by a variety of different mechanisms.…”