Hypoxia-triggered dichloroacetate delivery with effective reversal of cancer cell reprogramming

Dichloroacetate (DCA) is a known inhibitor of pyruvate dehydrogenase kinase, which is part of the key enzyme complex in metabolic reprogramming of cancer cells. In this work, we structurally modified dichloroacetate in an attempt to transform it into a more selective agent, which would deliver DCA selectively, only under hypoxic conditions. The 3-methyl-2-nitroimidazole dichloroacetate derivative studied in this work is a prodrug version of dichloroacetate, and it is active at lower concentrations in hypoxic cell cultures and suppresses tumor progression significantly in vivo. Both modules of the agent to be released after the reductive transformation have been tested as parts of various drugs, which have undergone clinical trials and deemed to be generally safe. Consequently, the DCA releasing prodrug investigated in this work has significant therapeutic potential as evidenced by viability assays, microscopy, flow cytometry, western blot and tumor model studies.