Fig. 2.

Metabolic targeting strategies against malignant tumors that rely on HK-2 facilitated glycolytic flux. The pyruvate analog 3-Br-pyruvate after entering tumor cells inhibits the function of both hexokinase-2 {1} and the ATP synthasome (ATP synthase/adenine nucleotide carrier/phosphate carrier complex) {2}. Peptide analogs of the HK-2 N-terminal, or small-molecules clotrimazole, bifanazole or methyl jasmonate, can dislodge HK-2 from VDAC {1}, depriving HK-2 of direct access to mitochondrial generated ATP and negating tolerance to G-6-P mediated product inhibition. Lactate efflux by the monocarboxylate transporters (MCTs) can be inhibited via small-molecule cinnamic acid derivatives, i.e., α-cyano-4-hydroxy cinnamic acid {3} or silenced via siRNA; tumor specific lactate dehydrogenase (LDH) isoforms can be silenced via siRNA {4}; the pyruvate analog dichloroacetate (DCA) can be administered to inhibit mitochondrial pyruvate dehydrogenase kinase (PDHK) {5}, which prevents “inactivation” of mitochondrial pyruvate dehydrogenase (PDH). The “active” PDH facilitates a high rate of influx of pyruvate into mitochondria, with concomitant up-regulation of the TCA cycle, resulting in an altered tumor-mitochondrial redox status; tumor specific pyruvate kinase (PK) can be silenced via siRNA to alter the glycolytic flux by inhibiting the formation of pyruvate {6}. Each of the above steps, which either target HK-2, the first step of the glycolytic pathway, or force the re-direction of pyruvate at the ultimate steps of the same, result in a highly disturbed metabolic status in the tumor mitochondria. This likely activates disruption of mitochondrial membrane integrity and release of cytochrome c to the cytoplasm, which in turn activates apoptotic cascades in the targeted tumor cells (MPTP, mitochondrial permeability transition pore).