Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress

Abstract

Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.

Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro

“…Inhibition of glycolysis with GW6471 has also been reported 44 . Cytotoxic effects of a combination of fenofibrate with glycolysis inhibitors have been reported and our lab discovered a similar mechanism for metformin cytotoxicity in MS1 VEGF angiosarcoma cells 17,45 . Further studies will be required to clarify the underlying mechanisms and pharmacological studies supporting PPARα- and NFκB-independence may be complemented by RNA interference (RNAi)-mediated ‘knock-down’ experiments.…”

The metabolic regulation of fenofibrate is dependent on dietary protein content in male juveniles of Nile tilapia (Oreochromis niloticus)

“…Another study also showed that Nile tilapia fed with low-energy diets (12•56 MJ/kg, 30 % protein) exhibited extremely poor growth and feed conversion efficiency with high mortality rates, compared with those fed with moderate-(16•75 MJ/kg, 40 % protein) and high-energy (20•93 MJ/kg, 50 % protein) diets (19) . Furthermore, fenofibrate was reported to exacerbate energy stress and cell death in three human tumour cell lines which had been induced energy stress by 2-deoxy-glucose (a glycolytic inhibitor) (35) . In agreement with these studies, increasing oxidative stress and HSI could further reflect the energy stress induced by fenofibrate in the low energy intake situation (LP-fed fish) (14•5 MJ/kg, Supplementary Table S1).…”

Tumor metabolism regulating chemosensitivity in ovarian cancer

“…Researches under in vitro and in vivo conditions demonstrate that concomitant use of 2-DG with inhibitors of lysosomal permeabilization increased its anti-tumor action, inducing mitochondrial damage and necrotic cell death [150]. As well, cotreatment of 2-DG with the PPARα agonist, fenofibrate (FF) leads to cancer cell death by inducing endoplasmic reticulum stress [151]. Despite these promising results, 2-DG clinical trials were stopped in phase I, since 2-DG resulted in intolerable hypoglycemia and reduced white blood cell counts in leukemia patients [152].…”