Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways

Farabegoli, Fulvia; Vettraino, Marina; Manerba, Marcella; Fiume, L.; Roberti, Marinella; Stefano, Giuseppina Di

doi:10.1016/j.ejps.2012.08.012

Cited by 134 publications

(84 citation statements)

References 37 publications

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“…Excluding FX-11, whose specificity of action has recently been questioned [70], none of the most active identified inhibitors has been extensively studied on human tumor models. The only small molecule inhibitor tested on cultured cancer cells representative of human tumors with different metabolic states and/or pathological subtypes is galloflavin [107,108]. However, this compound is active at quite high doses, when compared with conventionally used chemotherapeutics; moreover, it shows solubility problems hindering its administration in vivo.…”

Section: Conclusion and Future Perspectivementioning

confidence: 98%

“…Moreover, it was shown to be not harmful for mitochondrial respiration, suggesting tolerability for normal cell metabolism. In further studies aimed at better defining its therapeutic potential, GF was tested on breast cancer cell lines with different metabolic phenotypes and representative of different pathologic subtypes of the tumor [107]. In all the studied cell lines the IC 50 was in the 90-150 µM range and cell death was found to occur mainly through apoptosis.…”

Section: Structure-based Virtual Screeningmentioning

confidence: 99%

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Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

et al. 2014

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In the attempt of developing innovative anticancer treatments, growing interest has recently focused on the peculiar metabolic properties of cancer cells. In this context, LDH, which converts pyruvate to lactate at the end of glycolysis, is emerging as one of the most interesting molecular targets for the development of new inhibitors. In fact, because LDH activity is not needed for pyruvate metabolism through the TCA cycle, inhibitors of this enzyme should spare glucose metabolism of normal non-proliferating cells, which usually completely degrade the glucose molecule to CO2. This review is aimed at summarizing the available data on LDH biology in normal and neoplastic cells, which support the anticancer therapeutic approach based on LDH inhibition. These data encouraged pharmaceutical industries and academic institutions in the search of small-molecule inhibitors and promising candidates have recently been identified. The availability of inhibitors with drug-like properties will allow the evaluation in the near future of the real potential of LDH inhibition in anticancer treatment, also making the identification of the most responsive neoplastic conditions possible.

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Section: Conclusion and Future Perspectivementioning

confidence: 98%

Section: Structure-based Virtual Screeningmentioning

confidence: 99%

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

et al. 2014

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“…The evaluated proteins (BAX and BCL2) are well studied regulators of the mitochondrial apoptosis pathway [38]. Moreover, increased BAX levels were already found in cancer cells treated with oxamate [35] and other LDH inhibitors [27]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 96%

Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors

Rupiani

Buonfiglio

Manerba

et al. 2015

European Journal of Medicinal Chemistry

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“…LDH-A was initially found to be important for human Burkitt lymphoma clonogenicity (30,31) yet later it was shown to be essential for tumorigenesis (23,(32)(33)(34)(35). On the other hand, blocking LDH-A activity by its specific inhibitor oxamate or siRnA has been found to inhibit cell proliferation, induce G2/M cell cycle arrest and apoptosis, and sensitize tumor cells to ionizing radiation in several cancer types such as nasopharyngeal and GCs (36).…”

Section: Discussionmentioning

confidence: 99%

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

Liu

Yang

Chen³

et al. 2014

Oncology Reports

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Abstract. Lactate dehydrogenase A (LDH-A), which regulates glycolytic flux by catalyzing pyruvate to lactate in the cytoplasm, is believed to be one of the highly attractive therapeutic targets for cancers. Firstly, we detected the expression of LDH-A in gastric cancer (GC) cells. LDH-A inhibitor oxamate was then used to suppress the LDH-A activity in GC cells. Cell proliferation, lactic acid production, Transwell migration assay and apoptosis were assessed, respectively. The results showed that inhibition of LDH-A by oxamate decreased the lactate production. In the presence of glucose, oxamate inhibited cell proliferation in a dose-dependent manner. Flow cytometry assay further confirmed a pro-apoptotic effect of oxamate, and this was likely through increased expression of Bax, activated caspase-3, and decreased expression of Bcl-2. Therefore, we believe that oxamate inhibits cell growth, suppresses tumor invasion, and induces apoptosis in GC cells. LDH-A may be a potential therapeutic target for GC. IntroductionGastric cancer (GC) is one of the most common malignancies worldwide (1). Although the incidence has decreased in developed countries, it still remains an important public health burden in China (2). Globally, more than two-thirds of GC patients have unresectable disease at the time of diagnosis and 60% of resectable cases eventually relapse (3). The prognosis for advanced GC remains poor, with a 5-year survival rate of 26% (4). Therefore, more effective therapeutic approaches are urgently needed for GC patients.Altered metabolism is one of the critical hallmarks of cancers (5). Even in the presence of enough oxygen, tumor cells prefer to metabolize glucose by glycolysis rather than oxidative phosphorylation (6). In tumor cells, a substantial amount of pyruvate is reduced to lactate instead of being directed into the mitochondrion. Key alterations in metabolic pathways in tumor cells may create opportunities for the design of new anticancer approaches (7). In fact, agents targeting tumor metabolism have been proven useful in cancer therapy. In this aspect, traditional antimetabolites, such as methotrexate (MTX) and 5-fluorouracil (5-FU), have been used as chemotherapeutic agents for several decades (8). Most of these traditional antimetabolites target the final stages of the nucleotide synthesis and competitively inhibit the functioning of key enzymes involved in nucleic acid synthesis. However, these traditional anticancer agents only offer limited therapeutic benefits, and most of them are associated with severe adverse effects.Recent studies have indicated that deprivation of tumor cells of an energy supply can be a promising approach for cancer therapy. In mammalian cells, glucose is the key energy source for all tissues. Physiologically, glucose is converted to pyruvate via the glycolytic pathway, which is then either metabolized to lactic acid by lactic dehydrogenase (LDH) or enters the citric acid cycle in the matrix of the mitochondria (9). LDH-A is a cancer-specific isoform of LDH which convert...

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Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways

Cited by 134 publications

References 37 publications

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

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