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...

Malignant tumor cells are equipped with mechanisms that can help them escape the surveillance by host immune system. Immune checkpoint molecules can transduce coinhibitory signals to immunocompetent cells and exert immunosuppressive roles in antitumor immunity. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are the two important checkpoint molecules with great potential in targeted cancer therapy. Several antibodies targeting PD-1 and PD-L1 have been approved for clinical use. In this review, we focus on the recent development of targeting PD-1 and PD-L1 in gastric cancer (GC) therapy.

It has been confirmed that the inhibitors of poly ADP-ribose polymerF(^9ase-1 (PARP-1) can inhibit the proliferation, apoptosis and invasion of tumor cells. However, the effects of inhibitors of PARP-1 on hepatocellular carcinoma remain to be elucidated. The aim of the present study was to investigate the effect of three types of PARP-1 inhibitor on the proliferation, apoptosis and migration of hepatocellular carcinoma in vitro. An MTT assay was performed to detect the proliferation of HepG2 cells following treatment with the PARP-1 inhibitors, AG014699, BSI-201 and AZD-2281. Flow cytometry was used to detect the apoptosis of HepG2 cells, Western blot analysis was used to detect the protein expression of Casepase-3, Casepase-8, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, phosphatase and tensin homolog (PTEN), tissue inhibitor of metalloproteinase (TIMP) 3 and matrix metalloprotease (MMP) 3. A Transwell assay was performed to detect the migration of HepG2 cells. The results showed that AG014699, BSI-201 and AZD-2281 had an inhibitory effect on the proliferation of HepG2 cells in a time- and concentration-dependent manner. AG014699 at concentrations of 10, 30 and 50 µmol/l, and BSI-201 at concentrations of 20, 40 and 60 µmol/l induced the apoptosis of HepG2 cells, and the apoptotic rates were particularly high at 48 h (31, vs. 0.01%; P<0.01 and 24.12, vs. 0.03%, respectively; P<0.01). The protein expression levels of Caspase 3, Caspase 8, Bax, PTEN and TIMP 3 increased with increasing drug concentrations, whereas the protein levels of Bcl-2 and MMP3 decreased with increasing drug concentrations, and were significantly different compared with those in the control group (P<0.01). In conclusion, AG014699, BSI-201 and AZD-2281 inhibitors of PARP-1 significantly inhibited the proliferation of HepG2 cells, however, AG014699 and BSI-201 demonstrated more sensitivity, induced apoptosis and inhibited migration of the hepatocellular carcinoma cells, which may be associated with alterations of the apoptosis signaling pathway and the expression of proteins associated with migration.

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Here we assessed the predictive value of gamma-glutamyltransferase (γ-GT) for the prognosis of patients with HCC and compared the γ-GT with other prognostic factors. We retrospectively analyzed outcomes for 858 patients first diagnosed with HCC. Cox univariate and multivariate analyses receiver operating characteristic (ROC) curve were used for the study of significance of prognostic factor. A Kaplan-Meier survival analysis was performed to assess the value of γ-GT as an HCC prognostic factor in different classifications of Barcelona Clinic Liver Cancer (BCLC) or Tumor Node Metastasis (TNM) and different levels of serum alpha fetoprotein (AFP). We showed patient survival rates were significantly associated with γ-GT as well as serum biological markers including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), AFP. A γ-GT ≥ 75 U/L strongly indicated poor prognosis for HCC patients. The survival time of patients with γ-GT ≥ 75 U/L was significantly shorter in advanced BCLC and TNM stages and at any serum AFP level. All these results suggested that baseline γ-GT could effectively aid in determining the prognosis of patients with HCC, and the prognostic value of γ-GT ≥ 75 U/L was superior to that of Child-Pugh class, MELD stage, and serum AFP.