A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

Abstract

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

“…Cytotoxic drugs acting by selectively affecting mitochondria in cancer cells, 'mitocans' (Neuzil et al, 2006(Neuzil et al, , 2007Ralph et al, 2007), are attractive for the treatment of cancer (Ko et al, 2004;Bonnet et al, 2007;Dong et al, 2007;Neuzil et al, 2007). Prime examples of such drugs are a-tocopheryl succinate (a-TOS) (Neuzil et al, 2001a, b), 3-bromopyruvate (3BP) (Geschwind et al, 2002;Ko et al, 2004) and dichloroacetate (DCA) (Bonnet et al, 2007).…”

“…Prime examples of such drugs are a-tocopheryl succinate (a-TOS) (Neuzil et al, 2001a, b), 3-bromopyruvate (3BP) (Geschwind et al, 2002;Ko et al, 2004) and dichloroacetate (DCA) (Bonnet et al, 2007). 3BP inhibits the glycolytic pathway enzyme hexokinase, and succinate dehydrogenase (SDH), suppressing adenosine 5'-triphosphate production and mitochondrial respiration (Ko et al, 2001;Xu et al, 2005).…”

Interferon-β lipofection II. Mechanisms involved in cell death and bystander effect induced by cationic lipid-mediated interferon-β gene transfer to human tumor cells

“…30 Lipofected hIFNb gene depolarized the mitochondrial membrane In general, cancer cells display a basal hyperpolarization of the mitochondrial membrane that confers them a certain degree of resistance. 31 As it has been described in Figure 1c, M8 resulted resistant to rhIFNb protein compared with EW7 (IC 50 410 000 vs IC 50 : 800 IU ml À1 , respectively), whereas both cell lines resulted sensitive to hIFNb gene. One of the reasons of this difference may be because of the fact that only hIFNb gene depolarized mitochondrial membrane in M8 (Figure 4c), thus reverting the basal hyperpolarization displayed by this resistant cell line.…”

“…31 On the other hand, both rhIFNb protein and hIFNb gene decreased the mitochondrial membrane potential in EW7-sensitive cell line (Figure 7a). In addition, this decrease in mitochondrial potential was simultaneous to an increase in oxidative stress caused by hIFNb gene in both cell lines (Figure 7a and data not shown).…”

Trials and tribulations

“…In January this year, a study was published suggesting that a potential anticancer drug could inhibit tumour growth in rats 1 . But compared with many such studies published each year, this one has had a far larger impact.…”