Inhibition of Aerobic Glycolysis in Normal and Neoplastic Lymphoid Cells Induced by Lonidamine [1-(2,4-Dichlorobenzyl)-I-H-indazol-3-carboxylic acid]

Pg, Natali; Salsano, Felice; Viora, Marina; Nista, Anna; Malorni, Walter; Marolla, A; C, De Martino

doi:10.1159/000225879

Cited by 11 publications

(5 citation statements)

References 6 publications

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“…Interestingly, it seems to enhance aerobic glycolysis in normal cells, but suppresses glycolysis in cancer cells, likely through inhibition of the mitochondrially bound hexokinase (Floridi et al, 1981). Importantly, in vivo administration of lonidamine to a patient with B-cell chronic leukemia resulted in a decrease of lactate production comparable to that observed in vitro (Natali et al, 1984). Subsequent studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis in a dose-dependent manner leading to a decrease in cellular ATP (Floridi et al, 1998).…”

Section: Lonidaminementioning

confidence: 85%

Glycolysis inhibition for anticancer treatment

et al. 2006

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Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

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Section: Lonidaminementioning

confidence: 85%

Glycolysis inhibition for anticancer treatment

et al. 2006

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“…Lonidamine showed benefits in inhibiting glycolysis in cancer cells while increasing glycolysis in nontransformed cells. These pre-clinical studies evidenced Lonidamine as possessing merit as a chemotherapeutic [155,156,157]. Lonidamine reached phase III of clinical trials [158,159,160], however, there has not been further advancement with this agent recently.…”

Section: Implications For Cancer Therapy and Chemopreventionmentioning

confidence: 99%

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Justus

Sanderlin

Yang

2015

IJMS

126

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Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.

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“…Although the mechanism of action remains unclear, LND treatment is known to target metabolic pathways in cancer cells. Early studies based on reduced secreted lactate claimed that glycolysis was inhibited in LND-treated cells ( 16 , 23 , 24 ). This was proposed to arise through LND-mediated inhibition of mitochondrially bound hexokinase II, the enzyme that catalyzes the phosphorylation of glucose to glucose 6-phosphate once it enters the cell ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine

Guo

Shestov

Worth

et al. 2016

Journal of Biological Chemistry

146

133

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The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.

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Inhibition of Aerobic Glycolysis in Normal and Neoplastic Lymphoid Cells Induced by Lonidamine [1-(2,4-Dichlorobenzyl)-I-H-indazol-3-carboxylic acid]

Cited by 11 publications

References 6 publications

Glycolysis inhibition for anticancer treatment

Glycolysis inhibition for anticancer treatment

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine

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