D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

Abstract

Somatic mutations in isocitrate dehydrogenase (IDH)-1 and -2 have recently been described in glioma. This mutation leads to a neomorphic enzymatic activity as the conversion of isocitrate to alpha ketoglutarate (αKG) is replaced by the conversion of αKG to D-2-hydroxyglutarate (D-2HG) with NADPH oxidation. It has been suggested that this oncometabolite D-2HG via inhibition of αKG-dioxygenases is involved in multiple functions such as epigenetic modifications or hypoxia responses. The present study is aimed at deciphering how the mutant IDH can affect cancer pathogenesis, in particular with respect to its associated oncometabolite D-2HG. We show that the overexpression of mutant IDH in glioma cells or treatment with D-2HG triggered an increase in cell proliferation. However, although mutant IDH reduced cell sensitivity to the apoptotic inducer etoposide, D-2HG exhibited no effect on apoptosis. Instead, we found that the apoptotic effect was mediated through the mitochondrial NADH pool reduction and could be inhibited by oxamate. These data show that besides D-2HG production, mutant IDH affects other crucial metabolite pools. These observations lead to a better understanding of the biology of IDH mutations in gliomas and their response to therapy.

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

“…Conspicuously, the glioblastoma cell line had a characteristically low level of the expression all of the genes that were tested except LCK. Remarkably, the mRNA level for the IDH1 transcription was also the lowest among all of the cell lines that were investigated, which correlates well with the low basal level of IDH1 or the IDH1 R132H mutant in those U-251 cells, which was previously reported by Oizel et al [62] This also explains the relative resistance of glioblastoma cells to both the tosylamides and two other inhibitors. Specifically, TOS-1, which is slightly active against the LCK and CSK kinases, was more active against U-251 than the other compounds.…”

Glioma Subclassifications and Their Clinical Significance

“…While the specific mechanism of IDH mutation (and potentially 2HG) that results in the oncogenic switch in gliomas remains unknown, potential mechanisms have been identified, including inhibition of hypoxia-related proline hydroxylases, inhibition of DNA demethylases, inhibition of histone demethylases, and alterations in glumatate metabolism. Meanwhile, reduction of the mitochondrial NADPH pool can reduce sensitivity of cells to redox associated apoptosis [24] and may also contribute to tumor progression while increasing sensitivity to oxidative damage from radiation treatment. Further work is needed to elucidate the specific role of IDH mutation and the pathological consequences that clearly impact tumor evolution and prognosis.…”

Mitochondrial spare respiratory capacity: Mechanisms, regulation, and significance in non‐transformed and cancer cells

“…13 Acute myeloid leukemia (AML) cells presenting IDH mutations correspond to a subset of cells with even lower SRC levels. 88 One exception is chronic lymphocytic leukemia cells that have higher SRC levels than B cells probably due to the increase in mitochondrial content. 89 However, one drawback of the above studies is that SRC values were obtained from stable cancer cell lines cultured in vitro often in high glucose medium, a metabolic condition that may not adequately represent the in vivo situation.…”