Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction

Hassouni, Btissame El; Frańczak, Marika; Capula, Mjriam; Vonk, Christian M.; Gomez, Valentina M; Smolenski, Ryszard T.; Granchi, Carlotta; Peters, Godefridus J.; Minutolo, Filippo; Giovannetti, Elisa

doi:10.18632/oncoscience.519

Cited by 18 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The combination of HFD with Li-PIC3 resulted in increased ROS in the liver as compared to HFD alone, while other conditions were indistinguishable from one another. Additionally, expression of ldh1a and ggt , whose expression has been shown to be elevated in some liver diseases [ 40 , 41 ] and used here as surrogate measures of liver cell dysfunction, were unchanged from controls with either HFD or Li-PIC3 treatments alone. However, expression of these markers was dramatically upregulated (200- and 50-fold for ldh1a and ggt , respectively) in the Li-PIC3+HFD animals.…”

Section: Discussionmentioning

confidence: 99%

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

et al. 2022

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

et al. 2022

View full text Add to dashboard Cite

show abstract

“…LDH-A serves as a key enzyme for metabolic reprogramming, instant energy production, and maintaining tumor homeostasis in cancer cells [46]. As LDH-A is overexpressed and hyperactive in many cancers, a variety of reports suggest that inhibiting LDH-A leads to cell death, thus conferring the dependency of cancer cells on LDH-A [11, 12, 13].…”

Section: Discussionmentioning

confidence: 99%

“…In the hypoxic microenvironment of tumor cells, the transcription factors HIF-1α and c-myc are upregulated, which further upregulates LDH-A which has been identified as one of the key enzymes in causing the Warburg effect [9, 10]. It has already been well established that reduction of LDH-A expression or inhibition of its enzymatic activity leads to inhibition of tumor initiation and cell proliferation [11]. Thus, LDH-A is considered a novel target for a variety of anticancer drugs [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Malla,

Gupta,

Sur

2023

Preprint

View full text Add to dashboard Cite

Cancer cells exhibit a unique metabolic preference for choosing the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase-A (LDH-A) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a non-steroidal anti-inflammatory drug, has been shown to exhibit anti-cancer effects by interfering with the glucose metabolism pathway. However, the specific targets remain unknown. Usingin-silico, biochemical, and biophysical studies, we show that DCF binds to LDH-A adjacent to the substrate binding site and dose-dependently inhibits its activity in an allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF fails to induce cytotoxicity in LDH-A knocked-down HeLa cells, confirming that DCF renders its anti-mitotic effects via LDH-A inhibition. DCF-induced LDH-A inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism by which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates AMPK, a sensor kinase, which further downregulates p-S6K, leading to apoptosis-mediated cell death. We find that in LDH-A knocked-down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, implying the involvement of DCF-induced LDH-A inhibition in the activation of the AMPK/S6K signaling pathway.

show abstract

“…Thus, they increase GEM-containing DNA synthesis, affect the cell cycle and induce apoptosis, and substantially restore PC cell sensitivity to GEM ( Maftouh et al, 2014 ). NHI-Glc-2, a novel inhibitor, dual-targets LDHA and GLUT-1 and makes anti-cancer effects more pronounced in combination with GEM ( El Hassouni et al, 2020 ).…”

Section: Alterations In Glucose Metabolismmentioning

confidence: 99%

The role of metabolic reprogramming in pancreatic cancer chemoresistance

Liu

2023

Front. Pharmacol.

View full text Add to dashboard Cite

Pancreatic cancer is characterized by hidden onset, high malignancy, and early metastasis. Although a few cases meet the surgical indications, chemotherapy remains the primary treatment, and the resulting chemoresistance has become an urgent clinical problem that needs to be solved. In recent years, the importance of metabolic reprogramming as one of the hallmarks of cancers in tumorigenesis has been validated. Metabolic reprogramming involves glucose, lipid, and amino acid metabolism and interacts with oncogenes to affect the expression of key enzymes and signaling pathways, modifying the tumor microenvironment and contributing to the occurrence of drug tolerance. Meanwhile, the mitochondria are hubs of the three major nutrients and energy metabolisms, which are also involved in the development of drug resistance. In this review, we summarized the characteristic changes in metabolism during the progression of pancreatic cancer and their impact on chemoresistance, outlined the role of the mitochondria, and summarized current studies on metabolic inhibitors.

show abstract

Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction

Cited by 18 publications

References 19 publications

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

The role of metabolic reprogramming in pancreatic cancer chemoresistance

Contact Info

Product

Resources

About