Digitoxigenin Augments 2-Dg Induced Toxicity In Cancer Cells By Targeting Hypoxia-Induced Factor 1-[alpha]-Mediated Signaling

Accelerated glycolysis ensures ATP levels meet the demands of highly proliferating cancer cells. Cancer cells significantly differ from the normal cells in producing as much as 50% of the cellular ATP by anaerobic glycolysis. This differential metabolic profile is recently perceived as a target of n...

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Bibliographic Details
Published in:Indian journal of clinical biochemistry 2022-05, Vol.32 (S1), p.S13
Main Authors: Shukla, Akanchha, Dhawan, Garima, Singh, Romila, Rajawat, Jyotika, Singh, Manohar, Shukla, Nidhi, Jajoriya, Arun Kumar, Mishra, Divya, Mishra, D.P
Format: Article
Language:English
Subjects:
Cancer
Cancer cells
Cell death
Enzymes
Health aspects
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Summary:Accelerated glycolysis ensures ATP levels meet the demands of highly proliferating cancer cells. Cancer cells significantly differ from the normal cells in producing as much as 50% of the cellular ATP by anaerobic glycolysis. This differential metabolic profile is recently perceived as a target of novel therapeutic strategies. However, current therapeutic agents targeting glycolytic enzymes lack specificity, have off target effects and limited clinical potential. The glycolytic inhibitor, 2-Deoxy Glucose (2-DG) has been used as a therapeutic agent targeting hexokinase2 (HK2) enzyme in cancer. However, 2-DG treatment is known to induce prosurvival Akt /HIF1[alpha] signaling. Enhanced therapeutic efficacy has been observed with the combination of phosphatidylinositol-3-kinase/Akt inhibitors in 2-DG-based chemotherapy/radiotherapy. Cardiac glycosides induce potent anticancer activities by modulation of Src kinase signaling, induction of TRAIL, TNF [alpha], NF[alpha]B induced cell death, Topoisomerase II and HIF1[alpha] inhibition. Therefore, we studied the effects of a cardiac glycoside Digitoxigenin (DGX) in an effort to counter 2-DG induced pro-survival HIF1a signaling in Glioblastoma cells. Digitoxigenin enhanced cytotoxicity of 2-DG in a dose dependent manner showing synergistic effects. Combined treatment with subtoxic doses of 2-DG (1mM) and DGX (0.5 [micro]M) significantly reduced colony formation, invasion and migration in U87MG and LN229 glioblastoma cells. Protein profiling studies showed significant reduction of 2-DG induced HIF1[alpha], HK2 and other pro-survival protein expression. Thus, these results collectively suggest that the combined treatment of 2-DG and DGX inhibits proliferation, invasion and migration by targeting pro-survival HIF1? signaling in glioblastoma cells. In conclusion, this study revealed that in glioblastoma cells digitoxigenin augments 2-DG induced toxicity by targeting HIF1[alpha].
ISSN:0970-1915