COMPARATIVE STUDY OF SODIUM OXAMATE AND METFORMIN CYTOTOXICITY AGAINST LEWIS LUNG CARCINOMA CELLS UNDER ANCHORAGE-INDEPENDENT GROWTH
DOI:
https://doi.org/10.15407/exp-oncology.2025.02.188Keywords:
metastatic cells, anchorage-independent growth, sodium oxamate, metformin, cytotoxicityAbstract
Background. The effect of the inhibitors of glycolysis and oxidative phosphorylation on the altered metabolism of neoplasms is considered a promising method of antitumor therapy. However, most studies on the antimetastatic activity of such inhibitors focus on analyzing their effect on the migratory and invasive characteristics of cells. Meanwhile, the survival of circulating metastatic cells and their resistance to anoikis are critically important factors in metastasis. Aim. To carry out a comparative study of sodium oxamate (SOX) and metformin (MTF) effects on the survival, proliferative activity, and metabolic plasticity of the low-metastatic variant of Lewis lung carcinoma (LLC/R9) cells under their anchorage-independent growth. Materials and Methods. Cell death, apoptosis, cell cycle distribution, reactive oxygen species (ROS) production, glucose and lactate levels, and vimentin expression in LLC/R9 cells under their anchorage- independent growth were assessed following SOX and MTF treatments. Results. The cytotoxicity of inhibitors was manifested in a significant decrease in the number of viable LLC/R9 cells and an increase in the number of dead and apoptotic cells, the effects being more pronounced for MTF. In the case of SOX treatment, a correlation was observed between an increase in the percentage of apoptotic cells and ROS level and a decrease in the glucose consumption rate (GCR). MTF increased GCR and the number of apoptotic cells, without changes in ROS levels. Incubation with MTF resulted in a significant twofold increase in the percentage of cells in the S phase due to a decrease in the fraction of cells in the G1/G0 and G2/M phases of the cell cycle. Conclusions. Unlike SOX, the cytotoxic effect of MTF on de-adhesive cells was directly related to disrupting energy homeostasis and cell cycle regulation rather than by oxidative stress. Their combined application could potentially reinforce metabolic stress in circulating tumor cells, simultaneously weakening glycolytic and oxidative compensatory pathways, thereby limiting metastatic competence.
References
Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314. doi:10.1126/science.123.3191.309
Luengo A., Gui D.Y., Vander Heiden M.G. Targeting metabolism for cancer therapy. Cell Chem. Biol. 2017;24:1161- 1180. https://doi.org/10.1016/j.chembiol.2017.08.028
Kubik J, Humeniuk E, Adamczuk G, et al. Targeting energy metabolism in cancer treatment. Int J Mol Sci. 2022;23(10):5572. https://doi.org/10.3390/ijms23105572doi
Comandatore A, Franczak M, Smolenski RT, et al. Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers. Semin Cancer Biol. 2022;86(Pt 2):93-100. https://doi.org/10.1016/j.semcancer.2022.09.001
Sharma D, Singh M, Rani R. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol. 2022;87:184-195. https://doi.org/10.1016/j.semcancer.2022.11.007
Sheng SL, Liu JJ, Dai YH, et al. Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. FEBS J. 2012;279(20):3898‐3910.
Feng Y, Xiong Y, Qiao T, et al. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in can- cer therapy. Cancer Med. 2018;7(12):6124-6136. https://doi.org/10.1002/cam4.1820
Huang X, Li X, Xie X, et al. High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer.
Breast. 2016;30:39-46. https://doi.org/10.1016/j.breast.2016.08.014
Altinoz MA, Ozpinar A. Oxamate targeting aggressive cancers with special emphasis to brain tumors. Biomed Pharmacother. 2022;147:112686. https://doi.org/10.1016/j.biopha.2022.112686
Bridges HR, Jones AJ, Pollak MN, et al. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462(3):475-487. https://doi.org/10.1042/BJ20140620
Cai H, Li J, Zhang Y, Liao Y, et al. LDHA promotes oral squamous cell carcinoma progression through facilitating gly- colysis and epithelial-mesenchymal transition. Front Oncol. 2019;9:1446. https://doi.org/10.3389/fonc.2019.01446
Ghanbari Movahed Z, Rastegari-Pouyani M, Mohammadi MH, et al. Cancer cells change their glucose metabolism to overcome increased ROS: One step from cancer cell to cancer stem cell? Biomed Pharmacother. 2019;112:108690. https://doi.org/10.1016/j.biopha.2019.108690
Parlani M, Jorgez C, Friedl P. Plasticity of cancer invasion and energy metabolism. Trends Cell Biol. 2023;33(5):388- 402. https://doi.org/10.1016/j.tcb.2022.09.009
Solyanik GI, Pyaskovskaya ON, Garmanchouk LV. Cisplatin-resistant Lewis lung carcinoma cells possess increased level of VEGF secretion. Exp Oncol. 2003; 24: 260–265
Hnatiuk S, Kolesnyk D, Solyanik G. Biochemical features of glycolysis in cancer cells with different metastatic po- tential. Low Temp Phys. 2024;50(3):285-288. https://doi.org/10.1063/10.00249749
Payen VL, Porporato PE, Baselet B, et al. Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci. 2016;73(7):1333-1348. https://doi.org/10.1007/ s00018-015-2098-5
Bose S, Le A. Glucose metabolism in cancer. Adv Exp Med Biol. 2018;1063:3-12. https://doi.org/10.1007/978-3-319- 77736-8_1
Barba I, Carrillo-Bosch L, Seoane J. Targeting the Warburg effect in cancer: where do we stand? Int J Mol Sci. 2024;25(6):3142. https://doi.org/10.3390/ijms25063142
Halma MTJ, Tuszynski JA, Marik PE. Cancer metabolism as a therapeutic target and review of interventions. Nu- trients. 2023;15(19):4245. https://doi.org/10.3390/nu15194245
Berr AL, Wiese K, Dos Santos G, et al. Vimentin is required for tumor progression and metastasis in a mouse model of non-small cell lung cancer. Oncogene. 2023;42(25):2074-2087. https://doi.org/10.1038/s41388-023-02703-9
Zhao X, Liu L, Jiang Y, et al. Protective effect of metformin against hydrogen peroxide-induced oxidative damage in human retinal pigment epithelial (RPE) cells by enhancing autophagy through activation of AMPK pathway. Oxid Med Cell Longev. 2020;2020:2524174. https://doi.org/10.1155/2020/2524174
Park D, Lee S, Boo H. Metformin induces lipogenesis and apoptosis in h4iie hepatocellular carcinoma cells. Dev Reprod. 2023;27(2):77-89. https://doi.org/10.12717/DR.2023.27.2.77
Bonini MG, Gantner BN. The multifaceted activities of AMPK in tumor progression–why the “one size fits all” definition does not fit at all? IUBMB Life. 2013;65(11):889-896. https://doi.org/10.1002/iub.1213
Priebe A, Tan L, Wahl H, et al. Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells. Gynecol Oncol. 2011;122(2):389-395. https://doi.org/10.1016/j.ygyno.2011.04.024
Prasad A, Roy AC, Priya K, et al. Effect of differential deprivation of nutrients on cellular proliferation, oxida- tive stress, mitochondrial function, and cell migration in MDA-MB-231, HepG2, and HeLa cells. 3 Biotech. 2023;13(10):339. https://doi.org/10.1007/s13205-023-03759-w
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