Different effects of LDH-A inhibition by oxamate in non-small cell lung cancer cells

Abstract

Higher rate of glycolysis has been long observed in cancer cells, as a vital enzyme in glycolysis, lactate dehydrogenase A (LDH-A) has been shown with great potential as an anti-cancer target. Accumulating evidence indicates that inhibition of LDH-A induces apoptosis mediated by oxidative stress in cancer cells. To date, it's still unclear that whether autophagy can be induced by LDH-A inhibition. Here, we investigated the effects of oxamate, one classic inhibitor of LDH-A in non-small cell lung cancer (NSCLC) cells as well as normal lung epithelial cells. The results showed that oxamate significantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. As previous studies reported, LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest in H1395 cells. However, when being exposed to oxamate, A549 cells underwent autophagy as a protective mechanism against apoptosis. Furthermore, we found evidence that LDH-A inhibition induced G0/G1 arrest dependent on the activation of GSK-3β in A549 cells. Taken together, our results provide useful clues for targeting LDH-A in NSCLC treatment and shed light on the discovery of molecular predictors for the sensitivity of LDH-A inhibitors.

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

“…Inhibition of LDH-5 activity with oxamate, a classical inhibitor of gluconeogenesis, was shown to suppress cell proliferation through 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 induction of G2/M or G0/G1 cell cycle arrest and promotion of apoptosis mediated by oxidative stress in nasopharyngeal carcinoma (NPC) and NSCLC cells. These effects were respectively related to down regulation of CDK1/cyclin B1 or Akt-GSK-3β-cyclin D1 signaling pathways and enhanced formation of mitochondrial ROS [82,83]. Oxamate was also found to increase sensitivity to ionizing radiation in different NPC cell lines.…”

Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes

“…Therapeutic implications for high serum LDH levels were investigated in several types of cancer [27,28]. Koukourakis et al [27] reported some benefit of vatalanib (vascular endothelial growth factor tyrosine kinase receptor inhibitor) in colorectal cancer patients presenting high serum LDH levels.…”

“…The addition of vatalanib to FOLFOX 4 diminished the impact of LDH expression on the prognosis of patients. Yang et al [28] also examined the effects of oxamate, one classic inhibitor of LDH-A, in NSCLC cells. Oxamate significantly suppressed the proliferation of NSCLC cells, while it employed a much lower toxicity in normal cells.…”

Adipose tissue dysfunction and its effects on tumor metabolism

“…This accumulation of ROS resulted in increased incidence of apoptosis, suggesting that LDH-α is critical for tumor maintenance and cancer cell metabolism [274, 275]. These results have been recapitulated in a variety of diverse cancer types including lung cancer, renal cancer, breast cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, and pancreatic cancer [274, 276–282]. …”