Inhibition of lactic dehydrogenase as a way to increase the anti-proliferative effect of multi-targeted kinase inhibitors

Fiume, L.; Vettraino, Marina; Manerba, Marcella; Stefano, Giuseppina Di

doi:10.1016/j.phrs.2010.12.005

Cited by 36 publications

(26 citation statements)

References 22 publications

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“…In accordance to this suggestion a single experience of Fiume et al showed how inhibiting LDH production with oxamic acid in cancer cell lines potentiated the antiproliferative activity of tyrosine kinase inhibitors, such as sorafenib [24]. …”

Section: Discussionmentioning

confidence: 88%

The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management

et al. 2014

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BackgroundIn many tumour types serumlactate dehydrogenase (LDH) levels proved to represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis. As we previously reported LDH is an important predictive factor in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). Sorafenib represents the therapeutic stronghold in advanced HCC patients. As a tyrosine kinase inhibitor (TKI) mainly directed against the angiogenetic pathway, the correlation of sorafenib administration with markers of hypoxia could be an important tool in patients management. Aim of our analysis was to evaluate the role of LDH pre-treatment levels and its variation during treatment in HCC patients receiving sorafenib.Methods78 patients were available for our analysis. For all patients LDH values were collected within one month before the start of treatment and after the end of therapy. For study purposes we divided our patients into two groups, according to LDH pre-treatment levels, cut-off levels was determined with ROC curve analysis. Patients were, also, classified according to the variation in LDH serum levels pre- and post-treatment (increased vs decreased).ResultsPatients proved homogeneous for all clinical characteristics analyzed. In patients with LDH values under the cut-off median progression free survival (PFS) was 6.7 months, whereas it was 1.9 months in patients above the cut-off (p = 0.0002). Accordingly median overall survival (OS) was 13.2 months and 4.9 months (p = 0.0006). In patients with decreased LDH values after treatment median PFS was 6.8 months, and median OS was 21.0 months, whereas PFS was 2.9 months and OS 8.6 months in patients with increased LDH levels (PFS: p = 0.0087; OS: p = 0.0035).ConclusionsIn our experience, LDH seemed able to predict clinical outcome in terms of PFS and OS for HCC patients treated with sorafenib. Given the correlation between LDH levels and tumour angiogenesis we can speculate that patients with high LDH pretreatment levels may be optimal candidates for other emerging therapeutic agents or strategies targeting different molecular pathways.

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Section: Discussionmentioning

confidence: 88%

The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management

et al. 2014

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“…In our study, forced expression of LDHA in GH3 cells enhanced glucose uptake, lactate secretion and invasion. Suppression of LDHA by oxamate, which has great potential as a promising antitumor drug 28, 29 , reduced glucose uptake, lactate secretion and invasion in GH3 cells. Several studies have confirmed that MMP2 is closely related to the invasiveness of PA 30, 31 .…”

Section: Discussionmentioning

confidence: 99%

Lactate dehydrogenase A promotes the invasion and proliferation of pituitary adenoma

Zhang

et al. 2017

Sci Rep

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Lactate dehydrogenase A (LDHA) has been reported to be involved in the initiation and progression of tumors. However, the potential role of LDHA in pituitary adenoma (PA) remains unknown. In this study, we showed that the expression levels of LDHA mRNA and protein were significantly elevated in invasive PA samples, and positively correlated with higher Ki-67 index. Overexpression of LDHA in a PA cell line (GH3) promoted glucose uptake through the upregulation of glucose transporter-1 (Glut1), lactate secretion and induced cellular invasion by upregulation of matrix metalloproteinase2 (MMP2). LDHA also promoted GH3 cell proliferation through induction of cell cycle progression via activation of the Akt-GSK-3β-cyclinD1 pathway. Accordingly, oxamate-induced inhibition of LDHA suppressed glucose uptake, lactate secretion, invasion and proliferation in GH3 cells via down regulation of Glut1 and MMP2 expression and inhibition of the Akt-GSK-3β-cyclinD1 pathway. Moreover, oxamate induced GH3 cell apoptosis by increasing mitochondrial reactive oxygen species (ROS) generation. In vivo, LDHA overexpression promoted tumor growth, and oxamate delayed tumor growth. In primary PA cell cultures, oxamate also effectively suppressed invasion and proliferation. Our data indicate that LDHA is involved in promoting the progression of PA, and oxamate might be a promising therapeutic agent for the treatment of PA.

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“…A recent study has indicated that LDHA is up-regulated in HCC cells and promotes tumor growth and metastasis[38]. A series of clinical studies assessed the serum levels of LDH in HCC patients who were treated with hepatic resection[39,40], transarterial chemoembolization[41,42] and sorafenib[43,44] and found a similar conclusion that LDH may be an easily obtained biomarker for prognosis prediction and treatment selection for HCC patients.…”

Section: Reprogramming Of Glucose Metabolism-related Enzymes and Tranmentioning

confidence: 93%

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Shang

Wang

2016

WJG

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.

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Inhibition of lactic dehydrogenase as a way to increase the anti-proliferative effect of multi-targeted kinase inhibitors

Cited by 36 publications

References 22 publications

The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management

The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management

Lactate dehydrogenase A promotes the invasion and proliferation of pituitary adenoma

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

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