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Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease. [ABSTRACT FROM AUTHOR]