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T. Feinberg



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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-067 - Mitochondrial Respiration Capacity and Sensitivity to Glycolysis Blockade in Lung Cancer (ID 2360)

      09:30 - 17:00  |  Author(s): T. Feinberg

      • Abstract
      • Slides

      Background:
      One of the metabolic perturbations in cancer cells is the Warburg effect; glycolysis is preferred over oxidative phosphorylation (OXPHOS), even in the presence of oxygen. The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation may serve as an escape mechanism from apoptosis. Here, we aimed to profile the mitochondrial activity in different lung cancer cell lines in reference to their glycolytic activity and to their sensitivity to metabolic modifications.

      Methods:
      The metabolic profile of A549 and H358 cell lines were tested before and after glycolysis blockade (glucose starvation, 2DG) and mitochondrial induction (FCCP). Glycolysis inhibition and mitochondrial activity were assessed by western-blot quantification of key enzymes involved in the glycolysis pathway (e.g. Hexokinase I/II, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase 2) and of mitochondrial coded proteins (e.g. ND1, ATP6 synthase). The oxygen consumption rates (OCR) and extra cellular acidification rate (ECAR) were measured by XF[e]24 extracellular flux analyzer. Further, mitochondrial index was compared to the cells' sensitivity to glycolysis inhibition.

      Results:
      A549 cells were highly affected by glucose inhibition/starvation accompanied by ineffective mitochondrial compensation. On the other hand, H358 cells recovered completely from glucose starvation through mitochondrial hyper-activation (Fig 1); At the basal level (when no material was applied), A549 cells that were starved had a decrease of 68% in the ECAR, as compared to non-treated cells. Their recovery was limited after glucose injection (23 vs.41 mpH/min). In comparison, H358 cells had a 43% decrease in their glycolysis rate with a full recovery after glucose injection (44-46 mpH/min; pre & post respectively). Mitochondrial respiration was very low for A549 cells under starvation, while significantly increased in H358 cells (223 vs.143 pmol/min, *Pv<0.0001). Respectively, the expression level of mitochondrial coded proteins was higher in the cells that demonstrated higher mitochondrial capacity (Fig 2). Figure 1



      Conclusion:
      Cells with high mitochondrial capacity may tolerate glucose starvation/ blockade, while a limited mitochondrial reserve exposes the cells to higher sensitivity to glycolysis stress. This might suggest a potential therapeutic avenue with a companion predictive test.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      P2.04-047 - Mitochondrial Activation- A Potential Therapy in Lung Cancer (ID 2359)

      09:30 - 17:00  |  Author(s): T. Feinberg

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer related deaths in the United States with an overall 5- year survival rate of all stages of~ 17%. Radiation therapy plays a key role in lung cancer treatment. However, many lung cancer patients show resistance to radiation. There is a growing body of evidence indicating that mitochondria may be the primary targets for cancer therapeutics: The unique metabolism of most solid tumors, including lung cancer, stems from remodeling mitochondrial functions to produce a glycolytic phenotype and a strong resistance to apoptosis (Warburg effect). Cancer specific remodeling can be reversed by a small molecule named dichloroacetate (DCA) which promote mitochondrial activation by increasing the influx of pyruvate. Sodium oxamate- another molecule that interferes with cells metabolism, inhibits the formation of the lactate-the end product of glycolysis. Here, we tested whether mitochondrial induction (using DCA and sodium oxamate) may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Moreover we tested whether sodium oxamate, increases the effect of DCA on radiation.

      Methods:
      Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA and sodium oxamate. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity.

      Results:
      We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Sodium Oxamate radisosensitized H1299 cells as well. Double treatment with DCA and Sodium Oxamate enhances the radiosensitivity of H1299 cells.

      Conclusion:
      Mitochondrial activation may serve as a radio-sensitizer in the treatment of non-small cell lung cancer. Inhibition of the end stage of glycolysis increases the effect of mitochondrial activation on radiation.

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