Background: Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (such as iron) could play an important role in the regulation of the AMPK-dependent pathway regulating cellular energy homeostasis. This investigation examined the effect of the iron and copper chelator and potent anticancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on AMPK-mediated energy homeostasis. Methods and Results: These studies demonstrated that Dp44mT, which forms intracellular redox-active complexes with iron and copper, significantly activated AMPK (i.e., p-AMPK/AMPK ratio) in 5 different tumor cell-types. Furthermore, examination of the Dp44mT-metal complexes demonstrated that the effect of Dp44mT on AMPK was due to a dual mechanism: (1) its ability to chelate metal ion; and (2) the generation of reactive oxygen species (ROS). The activation of the AMPK pathway by Dp44mT was mediated by the upstream kinase, liver kinase B1 (LKB1), which is a known tumor suppressor. Moreover, using AMPKα1-selective silencing, we demonstrated that Dp44mT activated AMPK, resulting in inhibition of acetyl CoA carboxylase 1 (ACC1) and raptor, and activation of Unc-51 like kinase (ULK1). Conclusions: These effects are vital for inhibition of fatty acid synthesis, suppression of protein synthesis, and autophagic activation, respectively. Together, this AMPK-mediated repair response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. In conclusion, this study demonstrates for the first time that chelators target the AMPK-dependent energy homeostasis pathway.

Citation Format: Sukriti Krishan, Sumit Sahni, Des R. Richardson. The anticancer agent Dp44mT upregulates the AMPK-dependent energy homeostasis pathway in cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B142.