Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia

Maftouh, Mina; Avan, Amir; Sciarrillo, Rocco; Granchi, Carlotta; Leon, Lg; Rani, Reshma; Funel, Niccola; Smid, Kees; Honeywell, Richard J.; Boggi, Ugo; Minutolo, Filippo; Peters, Godefridus J.; Giovannetti, Elisa

doi:10.1038/bjc.2013.681

Cited by 146 publications

(127 citation statements)

References 59 publications

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“…The effects of Gal-4 on migration and invasion were evaluated as described previously [40]. Migration was investigated using the LeicaDMI300B (Leica) migration station integrated with the Scratch-Assay 6.1 software (Digital-Cell Imaging Labs, Keerbergen, Belgium).…”

Section: Methodsmentioning

confidence: 99%

Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma

et al. 2014

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Galectin-4 (Gal-4) has been recently identified as a pivotal factor in the migratory capabilities of a set of defined pancreatic ductal adenocarcinoma (PDAC) cell lines using zebrafish as a model system. Here we evaluated the expression of Gal-4 in PDAC tissues selected according to their lymph node metastatic status (N0 vs. N1), and investigated the therapeutic potential of targeting the cross-link with the Wnt signaling pathway in primary PDAC cells.Analysis of Gal-4 expression in PDACs showed high expression of Gal-4 in 80% of patients without lymph node metastasis, whereas 70% of patients with lymph node metastases had low Gal-4 expression. Accordingly, in primary PDAC cells high Gal-4 expression was negatively associated with migratory and invasive ability in vitro and in vivo. Knockdown of Gal-4 in primary PDAC cells with high Gal-4 expression resulted in significant increase of invasion (40%) and migration (50%, P<0.05), whereas enforced expression of Gal-4 in primary cells with low Gal-4 expression reduced the migratory and invasive behavior compared to the control cells. Gal-4 markedly reduces β-catenin levels in the cell, counteracting the function of Wnt signaling, as was assessed by down-regulation of survivin and cyclin D1. Furthermore, Gal-4 sensitizes PDAC cells to the Wnt inhibitor ICG-001, which interferes with the interaction between CREB binding protein (CBP) and β-catenin. Collectively, our data suggest that Gal-4 lowers the levels of cytoplasmic β-catenin, which may lead to lowered availability of nuclear β-catenin, and consequently diminished levels of nuclear CBP-β-catenin complex and reduced activation of the Wnt target genes. Our findings provide novel insights into the role of Gal-4 in PDAC migration and invasion, and support the analysis of Gal-4 for rational targeting of Wnt/β-catenin signaling in the treatment of PDAC.

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Section: Methodsmentioning

confidence: 99%

Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma

et al. 2014

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“…Nevertheless, some of them demonstrate high potential in combination with current therapies. It was recently showed that NHI-1 and -2 used together with gemcitabine enhanced the antiproliferative and anti-invasive activities of the chemotherapeutic drug, under both normoxia and hypoxia, in pancreatic ductal adenocarcinoma (PDAC) cell lines [85]. It was also found that NIH-2, combined with the redox-dependent bioreductive anticancer prodrug EO9, synergistically induced p53-positive cancer cell death [86].…”

Section: Synthetic Ldh-5 Inhibitors and Their Therapeutic Potentialmentioning

confidence: 99%

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

2015

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“…Small molecules named as NHI derivatives N-hydroxyindole derivatives endowed strong synergistic inhibitory effect on both enzyme as well as cell-based assays and also inhibited spheroid growth, cell migration and invasion in pancreatic cancer cells in combination with gemcitabine. These results offer a new hope in the development of new potent hLDH-5 inhibitors and their utilization in combination therapy for cancer treatment [12]. Very recently, the role and therapeutic potential of hLDH-5 enzyme in brain tumors has been investigated and found significant involvement of hLDH-5 in brain tumors and glioblastoma multiform.…”

mentioning

confidence: 88%

When Will Small Molecule Lactate Dehydrogenase Inhibitors Realize Their Potential in the Cancer Clinic?

Rani

Kumar

2017

Future Med. Chem.

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Keywords: cancer metabolism • drug discovery • hLDH5 inhibitors • tumor glycolysis • Warburg effectReaching beyond the success in development of anticancer drugs meant to precisely focus first on one hallmark of cancer and the production of a novel type of small molecules that are selective and specific for cancer treatment. Safety is a major challenge than the efficacy in the drug development processes of small molecules, for both the academic research and pharmaceutical industries. From a metabolic assessment, unlike normal cells, the most characteristic feature of cancer cells is an unusual metabolic profile exhibiting a high rate of glucose consumption and lactate production due to increased glycolytic activity to supply them sufficient energy and metabolites. This phenomenon, known as the 'Warburg effect' described the fact that the metabolic shift toward aerobic glycolysis is largely accepted as a key metabolic hallmark of cancer cells [1]. This metabolic alteration is independent of the availability of oxygen, resulting in increased levels of lactate and lower ATP production. Additionally, this metabolic trait provides a selective advantage for cancer cells to grow and proliferate and to support biomass synthesis even in the hypoxic environment. In fact, the 'glucose addiction' of cancer cells is considered to be an Achilles heel of cancer because of the highly susceptible nature of cancer cells to glucose withdrawal [2,3]. Is human lactate dehydrogenase-5 an innovative anticancer target?Recently, researchers from both academia and industries, have renewed interest in development of anticancer drugs by targeting human lactate dehydrogenase-5 (hLDH-5) and to explore the role of hLDH-5 in cancer initiation, growth and maintenance and its utility as a tumor biomarker. hLDH-5 enzyme occupies a crucial position in the Warburg effect and catalyzes the reduction of pyruvate coupled with the oxidation of nicotinamide adenine dinucleotide dehydrogenase (NADH) to form lactate and NAD (+) at the end in the final step of the glycolytic pathway. The NAD (+) thus obtained to determine the continuity of glycolysis [4]. Till date, the hLDH-5 isoform received a position in the list of highly promising hallmark of cancer, in other words, highly promising targets for cancer drug development and cancer treatment due to following main crucial facts such as: hLDH-5 isoform holds significant role as a metabolic checkpoint in the cancer glycolytic pathway; associations of this enzyme with the activation of some proto-oncogenes; its link with the maintenance of invasiveness and metastatic potential; and finally connection of hLDH-5 isoform to chemoresistance of cancer cells [5,6]. Is hLDH-5 a safe target?In our point of view, hLDH-5 isoform has significant functional roles in the development and survival of wide range of human cancers; thus, the total LDH activity and LDH isoform patterns could be utilized for diagnostic and prognostic significance and in neoplastic diseases. Kanno et al. found that the probable side effect mig...

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Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia

Cited by 146 publications

References 59 publications

Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma

Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

When Will Small Molecule Lactate Dehydrogenase Inhibitors Realize Their Potential in the Cancer Clinic?

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