Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells

Penso, Julia; Beitner, Rivka

doi:10.1016/s0014-2999(97)01507-0

Cited by 123 publications

(88 citation statements)

References 30 publications

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“…While a physiological increase in intracellular-free Ca 2+ increases mitochondrial-bound hexokinase and cytoskeleton-bound glycolytic enzymes, and thereby stimulates adenosine 5´-triphosphate (ATP) production, a high pathological rise in intracellular-free Ca 2+ causes a reduction in all the energy-producing systems in different cellular compartments, leading to cell death (Beery et al, 1980;Lilling and Beitner, 1990;Bassukevitz et al, 1992;Beitner and Lilling, 1993;Chen-Zion et al, 1993). Our experiments have also revealed that calmodulin antagonists are most effective drugs in the treatment of melanoma (Glass-Marmor et al, 1996;Glass-Marmor and Beitner, 1997;Beitner, 1998;Penso and Beitner, 1998).…”

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confidence: 71%

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Ca2+-induced changes in energy metabolism and viability of melanoma cells

1999

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Summary Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca 2+ ), induced by Ca 2+ -ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca 2+ -ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis. All these changes occurred at lower concentrations of the drug than those required to induce a reduction in viability of melanoma cells. We also found that low concentrations of Ca 2+ -ionophore induced an increase in adenosine 5′-triphosphate (ATP), which most probably resulted from the increase in mitochondrial-bound hexokinase, which reflects a defence mechanism. This mechanism can no longer operate at high concentrations of the Ca 2+ -ionophore, which causes a decrease in mitochondrial and cytosolic hexokinase, leading to a drastic fall in ATP and melanoma cell death. The present results suggest that drugs which are capable of inducing accumulation of intracellular-free Ca 2+ in melanoma cells would cause a reduction in energy-producing systems, leading to melanoma cell death.

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confidence: 71%

“…Separation and assay of mitochondrial-bound and soluble hexokinase from B16 melanoma cells was described previously (Penso and Beitner, 1998).…”

Section: Separation and Assay Of Bound And Soluble Enzymesmentioning

confidence: 99%

Ca2+-induced changes in energy metabolism and viability of melanoma cells

1999

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“…This can be accomplished via siRNA-mediated gene silencing techniques (Sui and Wilson, 2004). Additionally, what might be employed are small-molecule drugs such as Lonidamine (Fanciulli et al, 1996;Floridi et al, 1998) that inhibit HK activity, or analogs of the azole derivatives Clotrimazole [1-(alpha-2-chlorotrityl) imidazole] and Bifonazole [1-(alpha-biphenyl-4-ylbenzyl) imidazole] that act by interfering with HK-VDAC binding (Penso and Beitner, 1998), releasing the enzyme from mitochondria to the cytosol. Thus, apoptotic events may be promoted by either direct inhibition of HK activity, or via disruption of the 'guardian-role' mitochondria-bound HK plays in inhibiting induction of apoptosis.…”

Section: Hexokinase-mitochondrial Interactions As a Future Anticancermentioning

confidence: 99%

Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

2006

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“…One approach is based upon the observation that certain azoles, and clotrimazole in particular, effectively dissociate hexokinase from mitochondria. The underlying molecular basis of this effect is not known, but it does not appear to involve calcium metabolism or a direct mitochondrial effect of these agents (Penso and Beitner, 1998;Azoulay-Zohar and Aflalo, 2000). Another, more specific approach is based upon the observation that a chimeric protein containing the 15 amino-terminal hydrophobic residues of HKI binds to mitochondria and can be specifically displaced by the addition of increasing amounts of HKI (Gelb et al, 1992).…”

Section: Mitochondrial Hexokinases As Downstream Effectors Of Growth mentioning

confidence: 99%

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

2006

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Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt -also known as protein kinase B or PKB -is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

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Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells

Cited by 123 publications

References 30 publications

Ca2+-induced changes in energy metabolism and viability of melanoma cells

Ca2+-induced changes in energy metabolism and viability of melanoma cells

Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

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