The combination of tephrosin with 2-deoxy-D-glucose enhances the cytotoxicity via accelerating ATP depletion and blunting autophagy in human cancer cells.

Abstract

2-Deoxy-D-glucose (2-DG), a synthetic glucose analog that acts as a glycolytic inhibitor, is currently under clinical evaluation for targeting tumor cells. Tephrosin (TSN), a plant rotenoid, is known as an anticancer agent. In this study, we describe that the addition of TSN to 2-DG enhanced the cytotoxic activity of 2-DG against various types of cancer cells by accelerating ATP depletion and blunting autophagy. TSN increased the sensitivity of cancer cells to the cytotoxic effect of 2-DG. The combination of TSN and 2-DG induced acceleration of intracellular ATP depletion and the drastic activation of AMP-activated protein kinase (AMPK), which resulted in the inactivation of the mammalian target of rapamycin (mTOR) pathway. Of particular interest, TSN suppressed 2-DG-induced autophagy, a cell survival process in response to nutrient deprivation. We also showed that TSN inhibited 2-DG-induced activation of elongation factor-2 kinase (eEF-2K), which has been known to regulate 2-DG-induced autophagy. Inhibition of eEF-2K by RNA interference blunted 2-DG-induced autophagy and increased the sensitivity of cancer cells to the cytotoxic effect of 2-DG. The addition of TSN to 2-DG, however, did not enhance the cytotoxic activity of 2-DG by knockdown of eEF-2K, suggesting that inhibition of eEF-2K by tephrsoin could be a critical role in the potentiating effect of TSN on the cytotoxicity of 2-DG. Furthermore, we showed that the blunted autophagy and enhanced cytotoxicity of 2-DG was accompanied by the augmentation of apoptosis. These results show that TSN may be valuable for augmenting the therapeutic efficacy of 2-DG.

• Authors: Yunjin Choi, Jeong-Hyung Lee
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 12 Issue 11 Pg. 989-96 (Dec 01 2011) ISSN: 1555-8576 [Electronic] United States
• PMID: 22123175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Rotenone
• tephrosin
• Adenosine Triphosphate
• Deoxyglucose
• Elongation Factor 2 Kinase

Topics

• Adenosine Triphosphate (metabolism)
• Antineoplastic Combined Chemotherapy Protocols (toxicity)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Deoxyglucose (toxicity)
• Elongation Factor 2 Kinase (metabolism)
• Enzyme Activation (drug effects)
• Humans
• Intracellular Space (drug effects, metabolism)
• Neoplasms (metabolism)
• Rotenone (analogs & derivatives, toxicity)