A Novel Adenine Nucleotide Translocase Inhibitor, MT-21, Induces Cytochrome c Release by a Mitochondrial Permeability Transition-independent Mechanism

Machida, Kiyotaka; Hayashi, Yujiro; Osada, Hiroyuki

doi:10.1074/jbc.m204564200

Cited by 46 publications

(39 citation statements)

References 43 publications

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“…(Watabe et al, 2000;Machida et al, 2002) Paclitaxel Multiple neoplasias Can induce CsA-and Bcl-2-sensitive MOMP in isolated mitochondria, at high concentration.…”

Section: Mt21mentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…(Watabe et al, 2000;Machida et al, 2002) Paclitaxel Multiple neoplasias Can induce CsA-and Bcl-2-sensitive MOMP in isolated mitochondria, at high concentration.…”

Section: Mt21mentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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“…Cyclophilin D mutants R97A and H168Q were generated by site-directed mutagenesis using primer sets (5Ј-primer 5Ј-ACAAAGGCTCCACCTTCCACGCG-CAC-3Ј and 3Ј-primer 5Ј-CACCGCGTGGAAGGTGGAGCCTTTGT-3Ј) and (5Ј-primer 5Ј-GGATGGCAAGCAGGTTGTGTTCGGTC-3Ј and 3Ј-primer 5Ј-GACCGAACACAACCTGCTTGCCATCC-3Ј), respectively. Glutathione S-transferase-cyclophilin D fusion protein was prepared as described previously (23). PPIase activity was measured using a synthetic peptide, succinyl-Ala-Ala-Pro-Phe-4-nitroanilide, as a substrate in a two-step reaction coupled to chymotrypsin (24).…”

Section: Methodsmentioning

confidence: 99%

Suppression of Apoptosis by Cyclophilin D via Stabilization of Hexokinase II Mitochondrial Binding in Cancer Cells

Machida

Ohta

Osada

2006

Journal of Biological Chemistry

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124

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The permeability transition pore is involved in the mitochondrial pathway of apoptosis. Cyclophilin D, a pore component, has catalytic activity as a peptidyl prolyl cis, trans-isomerase (PPIase), which is essential to the pore opening. It has been reported that cyclophilin D overexpression suppresses apoptosis in cancer cells. To clarify the mechanism of this effect, we generated glioma cells overexpressing wild-type or a PPIase-deficient mutant of cyclophilin D. Interestingly, we found that the PPIase-dependent apoptosis suppression by cyclophilin D correlated with the amounts of mitochondrialbound hexokinase II, which has anti-apoptotic activity. Inactivation of endogenous cyclophilin D by small interference RNA or a cyclophilin inhibitor was found to release hexokinase II from mitochondria and to enhance Bax-mediated apoptosis. The anti-apoptotic effects of cyclophilin D were canceled out by the detachment of hexokinase II from mitochondria, demonstrating that mitochondrial binding of hexokinase II is essential to the apoptosis suppression by cyclophilin D. Furthermore, cyclophilin D dysfunction appears to abrogate hexokinase II-mediated apoptosis suppression, indicating that cyclophilin D is required for the anti-apoptotic activity of hexokinase II. Based on the above, we propose here that cyclophilin D suppresses apoptotic cell death via a mitochondrial hexokinase II-dependent mechanism in cancer cells.

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“…The bisphonate clodronate, which kills osteoclasts and is used for the palliative treatment of bone metastases, apparently is transformed into an ATP analogue which targets the ANT (Lehenkari et al, 2002). MT-21, an ANT inhibitot, has been shown to dissociate the ANT-cylophilin complex in vitro and to induce cytochrome c in isolated mitochondria in a reaction that is inhibited by bongkrekic acid (Machida et al, 2002). Lonidamine has been shown to revert the resistance to cisplatin and to potentiate cisplatin activity in experimental models.…”

Section: Ant Ligandsmentioning

confidence: 99%