Transarterial chemoembolization (TACE) may prolong the survival of patients with hepatocellular carcinoma (HCC); however, its efficacy is limited due to the high rate of incomplete embolization. Hypoxia after embolization can cause a series of changes in the tumor microenvironment, including lactate dehydrogenase A (LDHA) upregulation. Therefore, the current study assessed the antitumor effect and the underlying mechanism of the LDHA inhibitor, sodium oxamate (Ox), combined with TACE, using the rabbit VX2 liver tumor model. VX2 liver tumor models were created in the left liver lobe of rabbits, and after 14 days of treatments, the rabbits were sacrificed for the collection of the tumor tissues and blood samples. The antitumor effects of Ox, and the combination of Ox and TACE, and changes in the tumor microenvironment after treatments were assessed by histopathological evaluation, and the safety of the treatments was analyzed by measuring changes in the serum levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine. The results demonstrated that the combination of Ox and TACE notably improved antitumor effects compared with in the other groups, as it significantly inhibited tumor growth. Additionally, treatment with Ox + TACE downregulated vascular endothelial growth factor and matrix metalloproteinase-9, and enhanced the infiltration of CD3+ and CD8+ T cells into tumor tissues, thus suggesting that Ox + TACE may have a synergistic effect on increasing the infiltration of immune cells in the tumor microenvironment. With a well-tolerated and manageable impairment of hepatorenal function, targeting metabolic reprogramming could promote the efficacy of TACE, thus providing novel avenues for the future clinical management of patients with advanced HCC.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to the limited targeted therapies available at present. Cancer cells preferentially use glycolysis as their primary source of energy, characterized by increased glucose uptake and lactate production. JTC-801, a nociception/orphanin FQ opioid peptide (NOP) receptor antagonist, was reported to suppress the opioid receptor-like1 (ORL1) receptor/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB-mediated carbonic anhydrase 9 (CA9) signaling pathway. Sodium oxamate is an inhibitor of gluconeogenesis and a glycolysis inhibitor, as a competitive lactate dehydrogenase A (LDHA) inhibitor, which also produces tumor suppression due to loss of LDHA activity. However, the roles of opioid analgesic drugs (e.g., JTC-801) and glycolysis inhibitors (e.g., sodium oxamate) in TNBC have not fully been explored. Meanwhile, concurrent treatment with JTC-801 and sodium oxamate may cause synergistic anticancer effects in a TNBC model. In the present study, the combination of JTC-801 and sodium oxamate triggered cell death in the TNBC MDA MB-231 cell line. RNA-sequencing data revealed potential genes in the crosstalk between JTC-801 and sodium oxamate including ALDOC, DDIT4, DHTKD1, EIF6, ENO1, ENO3, FOXK1, FOXK2, HIF1A, MYC, PFKM, PFKP, PPARA, etc. The combination of JTC-801 and sodium oxamate provides a novel potential therapeutic strategy for TNBC patients via downregulating cell cycle- and amino acid metabolism-related pathways such as \"Cell cycle-the metaphase checkpoint\", \"(L)-tryptophan pathways and transport\", and \"Glutamic acid pathway\". Collectively, the present study demonstrated that the synergistic effect of co-treatment with JTC-801 and sodium oxamate significantly suppressed tumor growth and played a crucial role in tumor development, and in turn may serve as potential synergistic drugs for TNBC.

The study was performed to evaluate the effects of the reduced lactate production by sodium oxamate (SO) on growth performance, lactate and glucose and lipid metabolism, and glucose tolerance of Micropterus salmoides fed high-carbohydrate (CHO) diets. In in vitro study, primary hepatocytes were incubated for 48 h in a control medium (5.5 mM glucose), a high-glucose medium (25 mM glucose, HG), or a SO-containing high-glucose medium (25 mM glucose + 50 mM SO, HG-SO). Results indicated lactate and triglyceride (TG) levels, and lactate dehydrogenase a (LDH-a) expression in the HG-SO group were remarkably lower than those of the HG group. In in vivo study, M. salmoides (5.23 ± 0.03 g) were fed four diets containing a control diet (10% CHO, C) and three SO contents [0 (HC), 100 (HC-SO1), and 200 (HC-SO2) mg·kg-1, respectively] of high-CHO diets (20% CHO) for 11 wk. High-CHO diets significantly reduced weight gain rate (WGR), specific growth rate (SGR), p-AMPK-to-t-AMPK ratio, and expression of insulin receptor substrate 1 (IRS1), insulin-like growth factor I (IGF-I), insulin-like growth factor I receptor (IGF-IR), fructose-1,6-biphosphatase (FBPase), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyl transferase 1α (CPT1α) compared with the C group, whereas the opposite was true for plasma levels of glucose, TG, lactate, tissue glycogen, and lipid contents, and expression of LDH-a, monocarboxylate transporter 1 and 4 (MCT1 and MCT4), insulin, glucokinase (GK), pyruvate dehydrogenase E1 subunit (PDH), sterol-regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS). The HC-SO2 diets remarkably increased WGR, SGR, p-AMPK-to-t-AMPK ratio, and expression of IRS1, IGF-I, IGF-IR, GK, PDHα, PDHβ, FAS, acetyl-CoA carboxylase 1 (ACC1), PPARα, and CPT1α compared with the HC group. Besides, HC-SO2 diets also enhanced glucose tolerance of fish after a glucose loading. Overall, the reduced lactate production by SO benefits growth performance and glucose homeostasis of high-CHO-fed M. salmoides through the enhancement of glycolysis, lipogenesis, and fatty acid β-oxidation coupled with the suppression of glycogenesis and gluconeogenesis.

Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.

Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.

Based on our previous study, the low volatile fatty acid (VFA) production from egg white in food waste was mainly attributed to more acidogenic substrates (proteins and amino acids) consumed in the Maillard reaction and more organics converted into lactic acid. In this study, two methods were employed to improve VFA production: (1) reducing Maillard reaction with a drop in pH during hydrothermal (HT) pretreatment, and (2) inhibiting the conversion from protein to lactic acid. HT pretreatment under weakly acidic condition significantly promoted the hydrolysis and degradation of protein and the hydrolytic enzyme (protease) activity, thus increasing VFA yield by 45.8% from 0.24 to 0.35 g/g protein for HT pretreated egg white. Addition of sodium oxamate increased the maximal VFA yield from 0.24 to 0.29 g/g protein for HT pretreated egg white and from 0.32 to 0.67 g/g protein for egg white with no pretreatment in which there was more protein converted through the lactic acid metabolism pathway. Sodium oxamate improved the acidification step by inhibiting the reaction from pyruvates to lactic acid, and thereby accelerating the process of conversion from pyruvates to VFA.