2022 World Conference on Lung Cancer (ePosters)-EP07.01-008. Perturbation of Warburg Effect by Dichloroacetate and Niclosamide in Malignant Pleural Mesothelioma in Vitro and in Vivo

EP07.01-008. Perturbation of Warburg Effect by Dichloroacetate and Niclosamide in Malignant Pleural Mesothelioma in Vitro and in Vivo

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Researchers investigated the combination effect of two drugs, dichloroacetate (DCA) and niclosamide (Nic), on malignant pleural mesothelioma (MPM) both in vitro and in vivo. MPM is most commonly caused by inhalation of asbestos fibers, and although asbestos use is now regulated, the incidence of MPM continues to rise due to the long time it takes for the disease to develop. The current treatment options for MPM have a poor prognosis, so new treatments are urgently needed.<br /><br />Using a panel of MPM cell lines, the researchers conducted various experiments to evaluate the effect of the DCA/Nic combination. They found that the combination reduced cell viability synergistically in all cell lines. The drugs also disrupted the glycolysis and oxidative phosphorylation processes, leading to downregulation of glycogen, citrate, and succinate. Furthermore, the drugs induced apoptosis, depolarization of mitochondrial transmembrane potential, G2/M cell cycle arrest, and reactive oxygen species production. They also suppressed cell migration and colony formation.<br /><br />The researchers confirmed these findings in xenograft models of MPM in mice. The DCA/Nic combination showed a better initial tumor suppressive effect compared to either drug alone. In one xenograft model, DCA and DCA/Nic increased median survival of the mice. The drugs also increased intratumoral glycogen, citrate, and succinate levels while downregulating Bcl-2 and PARP. In another xenograft model, the DCA/Nic combination increased median survival compared to single treatments and suppressed tumor growth. It also affected various proteins involved in apoptosis, cell cycle regulation, and migration.<br /><br />Overall, the researchers concluded that DCA and/or Nic have a tumor suppressive effect on MPM, both in vitro and in vivo. This effect is mediated through disruption of glycolysis and oxidative phosphorylation, induction of apoptosis, production of reactive oxygen species, cell cycle arrest, and suppression of migration and proliferation. These findings suggest that the combination of DCA and Nic may be a potential treatment option for MPM.

Asset Subtitle

James C Ho

Meta Tag

Speaker James C Ho

Topic Mesothelioma, Thymoma, and Other Thoracic Malignancies - Clinical

Keywords

combination effect

dichloroacetate

niclosamide

malignant pleural mesothelioma

cell viability

glycolysis

apoptosis

xenograft models

tumor suppressive effect

treatment option