Relationship of mitochondrial function and cellular adenosine triphosphate levels to pMC540 and merodantoin cytotoxicity in MCF-7 human breast cancer cells

Gulliya, Kirpal S.; Sharma, Radhakant; Liu, Hwan-Wun; Arnold, Lauren; Matthews, James L.

doi:10.1097/00001813-199508000-00007

Cited by 6 publications

(2 citation statements)

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“…Because of their (photo)toxic effects, potentiometric fluorescent probes are in fact under investigation as potential therapeutic agents against various types of tumors [83–85], which appear to accumulate these molecules more efficiently than normal, non transformed cells. In this context it is worth mentioning that merocyanine, one of the first Δψ m probes in isolated mitochondria, is a powerful inducer of apoptosis [86,87], a finding that does support a role for mitochondria in the execution of the cell death program. Thus, if dye concentrations and exposure times are not thoroughly tested, the fluorescent probes could contribute to cause or potentiate rather than simply measure the changes of Δψ m .…”

Section: Measurements Of the Mitochondrial Membrane Potentialmentioning

confidence: 99%

Mitochondria and cell death

Bernardi

Scorrano

Colonna

et al. 1999

European Journal of Biochemistry

670

495

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Mitochondria are involved in cell death for reasons that go beyond ATP supply. A recent advance has been the discovery that mitochondria contain and release proteins that are involved in the apoptotic cascade, like cytochrome c and apoptosis inducing factor. The involvement of mitochondria in cell death, and its being cause or consequence, remain issues that are extremely complex to address in situ. The response of mitochondria may critically depend on the type of stimulus, on its intensity, and on the specific mitochondrial function that has been primarily perturbed. On the other hand, the outcome also depends on the integration of mitochondrial responses that cannot be dissected easily. Here, we try to identify the mechanistic aspects of mitochondrial involvement in cell death as can be derived from our current understanding of mitochondrial physiology, with special emphasis on the permeability transition and its consequences (like onset of swelling, cytochrome c release and respiratory inhibition); and to critically evaluate methods that are widely used to monitor mitochondrial function in situ.Keywords: mitochondria; cell death; apoptosis; necrosis; permeability transition; calcium; caspases; fluorescence; probes; cytochrome c.Mitochondria are central to the life of eukaryotic cells. In recent years, it has become clear that mitochondria also play a key role in the pathways to cell death [1±8]. This role of mitochondria cannot be explained by a mere`loss of function' resulting in an energetic deficit. Rather, it is increasingly recognized as aǹ active' process mediated by regulated effector mechanisms in a wide variety of conditions. A large body of observations from the fields of immunology, toxicology, oncology, neurology and cardiology testifies about the centrality of this issue. However, the general reader is probably puzzled by the growing number of conflicting reports, and by the diverging conclusions reached by different groups when mechanistic issues are addressed and/ or cause-relationship effects are discussed. A clear example is represented by the question of cytochrome c release, and of how this event relates to mitochondrial respiration, maintenance of the mitochondrial membrane potential difference (Dc m ) and volume homeostasis.In our opinion, part of the problem resides in the intrinsic difficulties one faces when measuring`mitochondrial function' in intact cells, an issue that is not always adequately appreciated. Mitochondrial responses in vivo may be extremely hard to decipher, and a large discrepancy currently exists between our understanding of mitochondrial function in the isolated organelle and in the intact cell. However, an acceptable description of in vivo events must always take into account facts and concepts established in decades of in vitro studies. Also, it should be realized that discrepancies may arise from inapparent differences in the experimental conditions, but also from artifacts or misinterpretation of the in situ experiments. As should become clear later in the revie...

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Section: Measurements Of the Mitochondrial Membrane Potentialmentioning

confidence: 99%

Mitochondria and cell death

Bernardi

Scorrano

Colonna

et al. 1999

European Journal of Biochemistry

670

495

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“…10 In fact, POP were reported to elicit a wide variety of effects, such as oxidation of proteins and unsaturated lipids, modulation of the immunologic response, 10,11 and inhibition of the growth of an EL4 tumor, which represents an experimental murine model of human CTCL. 11 The effect of the exposure to light of a photosensitizer prior its use in biological systems was also referred to as "preactivation" by Gulliya et al [12][13][14] In the case of photoactive compounds that were irradiated with visible light, such as merocyanine 540, naphthalimide, and Photofrin II, the "preactivation" protocol was successfully exploited for antiviral and antitumor therapeutic approaches. [15][16][17][18] Here we show that POPs caused apoptosis in Jurkat cells, thus highlighting the relevance of long-lasting toxic molecules generated by psoralen photodegradation.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy

Caffieri

Lisa

Bolesani

et al. 2007

Blood

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The generation of photoproducts of psoralen (POPs) might be relevant in cell death induced by psoralen plus UVA, namely PUVA, which is a recognized effective treatment for cutaneous T-cell lymphoma, chronic graft-versus-host disease, and psoriasis. We investigated the occurrence of POP-induced cell death and the underlying mechanisms. POPs were produced by irradiating a psoralen solution with UVA. Jurkat cells treated in the dark with these mixtures died mainly through an apoptotic mechanism. POPs were separated by high-performance liquid chromatography (HPLC), and cells were added with each of these fractions. A total of 2 dimers of psoralen and 6-formyl-7-hydroxycoumarin (FHC) were identified in the apoptogenic fractions. Apoptosis was preceded by mitochondrial dysfunction caused by the opening of the mitochondrial permeability transition pore (PTP). In fact, both mitochondrial depolarization and cell death were prevented by the PTP inhibitor cyclosporin A (CsA). PTP opening was also documented in isolated mitochondria added with POP, suggesting that apoptosis is caused by a direct effect of POP on mitochondria. In fact, FHC alone induced PTP opening and CsA-inhibitable cell death of Jurkat cells, whereas nontransformed T lymphocytes were resistant. Along with identifying novel apoptogenic molecules, the present results indicate that POP generation directs transformed cells to apoptosis. IntroductionThe combination of psoralens and UVA irradiation, which is commonly referred to as PUVA, represents a therapeutic approach useful in the treatment of cutaneous T-cell lymphoma (CTCL) 1 as well as skin diseases such as psoriasis and vitiligo. 2 In particular, the combination of interferon ␣-2a with oral photochemotherapy (PUVA) resulted in 70% complete remission in patients with CTCL. 1 A modified PUVA protocol is called extracorporeal photopheresis. This treatment involves the mechanical separation of mononuclear white cells, which are treated with psoralen and exposed to UVA light, and then returned to the patient. 3 Besides CTCL, extracorporal photopheresis is a recognized effective treatment modality in chronic graft-versus-host disease. 4 Different mechanisms have been related to PUVA cytotoxicity. 5 Besides the generation of reactive oxygen species, psoralen has been shown to bind covalently to and cross-link DNA. 6 Laskin and coworkers demonstrated that mammalian cells have specific highaffinity receptor sites for psoralens, distinct from DNA, but their molecular characterization has been not elucidated yet. 7 More recently, PUVA treatment has been reported to cause cell death by apoptosis, 8 and we have demonstrated that the underlying mechanism involves mitochondrial dysfunction caused by opening of the permeability transition pore (PTP). 9 On the other hand, upon UVA irradiation, psoralen photoproducts (POPs) are generated, which are likely to contribute to PUVA cytotoxicity. 10 In fact, POP were reported to elicit a wide variety of effects, such as oxidation of proteins and unsaturated lipids, modulation...

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The Role of Topoisomerases and Apoptosis in the Mechanism of Action of Preactivated Compounds

Gulliya

1996

Novel Chemotherapeutic Agents: Preactivation in the Treatment of Cancer and AIDS

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Relationship of mitochondrial function and cellular adenosine triphosphate levels to pMC540 and merodantoin cytotoxicity in MCF-7 human breast cancer cells

Cited by 6 publications

References 0 publications

Mitochondria and cell death

Mitochondria and cell death

The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy

The Role of Topoisomerases and Apoptosis in the Mechanism of Action of Preactivated Compounds

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