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Aerobic glycolysis reduces pyruvate flux into mitochondria, preventing a complete oxidation of glucose and shunting glucose to anabolic pathways essential for cell proliferation. Here we tested a new strategy, mitochondrial uncoupling, for its potential of antagonizing the anabolic effect of aerobic glycolysis and for its potential anticancer activities. Mitochondrial uncoupling is a process that facilitates proton influx across the mitochondrial inner membrane without generating ATP, stimulating a futile cycle of acetyl- CoA oxidation. We tested two safe mitochondrial uncouplers, NEN niclosamide ethanolamine and oxyclozanide, on their metabolic effects and anti-cancer activities. We used metabolomic NMR to examine the effect of mitochondrial uncoupling on glucose metabolism in colon cancer MC38 cells. Moreover, mitochondrial uncoupling inhibits cell proliferation and reduces clonogenicity of cultured colon cancer cells. Our data highlight a unique approach for targeting cancer cell metabolism for cancer prevention and treatment, identified two prototype compounds, and shed light on the anti-cancer mechanism of niclosamide. Introduction During the first half of the 20th century, Otto Warburg observed that cancer cells metabolize glucose in a distinct manner 1 , 2. Recent work in cancer cell metabolism has led to the elucidation of the significance of the Warburg effect to cancer 3 , 4. In essence, glycolysis in non-dividing cells is followed by complete oxidation of pyruvate in mitochondria, producing the end product of CO2.

Recent work in cancer cell metabolism has led to the elucidation of the significance of the Warburg effect to cancer 3 , 4. - A Free Solution to all your PDF Problems

In essence, glycolysis in non-dividing cells is followed by complete oxidation of pyruvate in mitochondria, producing the end product of CO2. This leads to a complete oxidation of glucose without biomass accumulation.

In contrast, in cancer cells, the pyruvate flux into mitochondria is reduced as the result of aerobic glycolysis. These pathways generate NADPH and metabolic intermediates such as ribose, providing the reducing agent and building blocks for biosynthesis required for biomass accumulation needed for cell proliferation 3 — 5.

Thus, targeting aerobic glycolysis, which in turn diminishes the production of reducing agents and building blocks for cancer cell biosynthesis, can be an effective and likely a universal anti-cancer strategy. Inside mitochondria, as illustrated in Fig.

The electrons then feed into the electron transport chain ETC residing in the mitochondrial inner membrane, which pumps protons out across the membrane and generates a proton gradient. Usually, the ETC activity is coupled to the energy requirement of the cells. When the energetic requirement is met, ETC and oxidation of acetyl-CoA are shut down, along with pyruvate flux into mitochondria. Mitochondrial uncoupling is a process that leads to proton influx across the mitochondrial inner membrane without passing through ATP synthase 6 — 9.

As illustrated in Fig.

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To meet the cellular energy demand, the flux of pyruvate into mitochondria is expected to accelerate, which promotes the complete oxidation of glucose. This mode of metabolic change induced by mitochondrial uncoupling could potentially diminish the anabolic effect of aerobic glycolysis.

Niclosamide was an FDA approved anthelmintic drug for treating tapeworm infection 11 , Its mechanism of action is to uncouple mitochondria 11 — Recent studies have found that niclosamide has strong in vitro anti-cancer activity against a wide arrange of cancer cells, including cells from colon cancer 14 , 15 , breast cancer 16 — 20 , glioma 21 , hepatocellular carcinoma 22 , adrenocortical carcinoma 23 , ovarian tumor 24 , osteosarcoma 25 , prostate cancer 26 , 27 , and many other cancer types 28 , Oxyclozanide is another mitochondrial uncoupling anthelmintic drug approved for veterinary use Oxyclozanide has not yet been reported in literature to have any anti-cancer activity.


We decided to use niclosamide and oxyclozanide as prototype drugs to examine the impact of mitochondrial uncoupling on cancer glucose metabolism and to determine their potential anti-cancer activities and particularly in vivo anticancer efficacy. NEN niclosamide ethanolamine is the ethanolamine salt of niclosamide, which has a similar excellent safety profile as niclosamide 11 , 12 , 32 , 33 and better systemic exposure Our recent studies showed that NEN has high levels of distribution in the liver after oral administration, where it uncouples mitochondria, reduces liver steatosis, and increase insulin sensitivity By reducing the number of colors, bit PNG files can be converted to much smaller 8-bit indexed color images.

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