Isothiocyanates. A new class of uncouplers

Miko, M; Chance, Britton

doi:10.1016/0005-2728(75)90031-6

Cited by 36 publications

(15 citation statements)

References 21 publications

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“…However, both cyclosporin A and bongkrekic acid in our hands did not inhibit the BITC-and PEITC-induced loss of DW m , suggesting that the ITCs likely do not modulate mitochondrial permeability transition pore, which is in line with what was reported by Rose et al (43). Several synthetic ITCs, including p-bromophenyl ITC, 4,4V -diisothiocyanatebiphenyl, and h-naphthylmethyl ITC, were shown to act on isolated liver mitochondria as uncouplers with stimulation of ATPase activity (46). However, disruption of DW m by a mitochondrial uncoupler, such as carbonyl cynide m-chlorophenylhydrazone, was not followed by cytochrome c release and cell death, and additional triggers were required for induction of apoptosis (47,48).…”

Section: Discussionsupporting

confidence: 91%

“…Certainly, higher lipid solubility facilitates the delivery of the compound to the membrane. In fact, Miko and Chance reported that the uncoupling activities of some ITCs positively correlated with their logP values (46). The importance of lipophilicity is also reflected by the damaging of the cell surface membrane.…”

Section: Discussionmentioning

confidence: 99%

“…1 Mitochondria are the major site of reactive oxygen species production, which may result from disruption of the respiratory chain (52 -54). Although mitochondrial respiration was suppressed by several ITCs including BITC (23,46,55), it remains to be determined to what extent reactive oxygen species production mediates ITC-induced damage of mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells

Tang

Zhang

2005

Molecular Cancer Therapeutics

140

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Many isothiocysanates (ITC) are promising cancerpreventive agents, and induction of apoptosis is one of their underlying mechanisms of action. We recently found that caspase-9 was preferentially activated over other initiator caspases in human bladder cancer UM-UC-3 cells. We report here that caspase-9 activation is the major step leading to ITC-induced apoptosis in this cell line. More importantly, our results show that caspase-9 activation by the ITCs may result primarily from mitochondrial damage. Four common naturally occurring ITCs were studied, including allyl ITC, benzyl ITC (BITC), phenethyl ITC (PEITC), and sulforaphane. BITC and PEITC showed more potent mitochondria-damaging ability than the other two ITCs, correlating well with their stronger apoptosis-inducing potentials. Furthermore, BITC and PEITC damaged both the outer and inner mitochondrial membranes. Use of isolated mitochondria allowed us to establish that ITCs, and more importantly their major intracellular derivatives (glutathione conjugates) at concentrations that are readily achievable in cells, damage mitochondria, leading to the collapse of mitochondrial trans-membrane potential and release of cytochrome c. The mitochondria-damaging potencies of the ITCs correlate well with their lipophilicities. Bcl-2 family members are known to influence the stability of mitochondrial membrane. Our results show that the ITCs caused phosphorylation of Bcl-2, induced mitochondrial translocation of Bak, and disrupted the association of Bcl-xl with both Bak and Bax in mitochondrial membrane, indicating that ITCinduced mitochondrial damage results at least in part from modulation of select Bcl-2 family members. [Mol Cancer Ther 2005;4(8):1250 -9]

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells

Tang

Zhang

2005

Molecular Cancer Therapeutics

140

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“…The exact mechanism by which ITC or their GSH conjugates damage mitochondria remains largely unknown. Several synthetic ITC, including p-bromophenyl ITC, 4,4 0 -diisothiocyanatebiphenyl and b-naphthylmethyl ITC, have been shown to uncouple oxidative phosphorylation (Miko & Chance, 1975) . Mitogen-activated protein kinases may also play a role in ITC-induced mitochondrial damage, as described later.…”

Section: Isothiocyanates Damage Mitochondria and Generate Reactive Oxmentioning

confidence: 99%

Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action

Zhang

Yao

2006

Proc. Nutr. Soc.

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Many isothiocyanates (ITC), which are available to human subjects mainly through consumption of cruciferous vegetables, demonstrate strong cancer-preventive activity in animal models. Human studies also show an inverse association between consumption of ITC and risk of cancer in several organs. Whereas earlier studies primarily focused on the ability of ITC to inhibit carcinogen-activating enzymes and induce carcinogen-detoxifying enzymes, more recent investigations have shown that ITC inhibit the proliferation of tumour cells both in vitro and in vivo by inducing apoptosis and arresting cell cycle progression. ITC cause acute cellular stress, which may be the initiating event for these effects. These findings shed new light on the mechanism of action of ITC and indicate that ITC may be useful both as cancer-preventive and therapeutic agents. ITC activate caspase 9-mediated apoptosis, apparently resulting from mitochondrial damage, and also activate caspase 8, but the mechanism remains to be defined. Cell cycle arrest caused by ITC occurs mainly in the G 2 /M phase, and both the G2 and M phases are targetted; critical G 2 -phase regulators, including cyclin B1, cell division cycle (Cdc) 2 and Cdc25C, are down regulated or inhibited, and tubulin polymerization and spindle assembly are disrupted. Moreover, ITC are metabolized in vivo through the mercapturic acid pathway, giving rise to thiol conjugates (dithiocarbamates). Studies show that these dithiocarbamates are similar to their parent ITC in exerting anti-proliferative activity. Taken together, dietary ITC are highly-promising anti-cancer agents, capable of targetting multiple cellular components that are important for tumour cell survival and proliferation.

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“…This effect of 2,4-dinitrophenol could be duplicated by a dozen variously substituted nitro-or halophenols, but not all such substituted derivatives were active (3). In the intervening years, the list of compounds that can replace 2,4-dinitrophenol in blocking the link between electron transfer and ATP synthesis without affecting electron transfer has grown considerably, and these compounds represent a wide variety of chemical structures (4)(5)(6)(7)(8). Somehow, the term uncoupler has become common for describing the compounds that block the link of electron transfer to ATP synthesis, and the term uncoupling is now usually applied to the process by which this block is achieved.…”

mentioning

confidence: 99%

Mechanism of uncoupling in mitochondria: uncouplers as ionophores for cycling cations and protons.

Kessler¹,

Tyson²,

Green³

1976

Proc. Natl. Acad. Sci. U.S.A.

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(3). In the intervening years, the list of compounds that can replace 2,4-dinitrophenol in blocking the link between electron transfer and ATP synthesis without affecting electron transfer has grown considerably, and these compounds represent a wide variety of chemical structures (4)(5)(6)(7)(8). Somehow, the term uncoupler has become common for describing the compounds that block the link of electron transfer to ATP synthesis, and the term uncoupling is now usually applied to the process by which this block is achieved. This is unfortunate, for implicit in the term uncoupling is the notion that a coupled process is replaced by an uncoupled process, and this notion is undoubtedly incorrect. However, it is too late to eliminate this usage from the scientific literature. We shall use the term uncoupling to denote the substitution of one coupled process by another mediated by the uncoupler, and the term uncoupler merely as the reagent that executes uncoupling so defined.Evidence will be presented that all uncouplers that duplicate by the uncoupler; (iii) the elimination of all protonic and cationic gradients generated across the mitochondrial membrane; (iv) no discrimination in these actions between one coupling site and another; and (v) no discrimination between coupled processes driven by electron transfer and coupled processes driven by ATP hydrolysis (3-5; 9-13). We shall define as a classical uncoupler any species that shows all these five properties and exclude from this definition any species that shows one or more, but not all, of these properties (see footnotet for a listing of the reagents that we now classify as pseudo uncouplers and not as classical uncouplers). The combination of two ionophores (valinomycin and nigericin) in the presence of K+ can duplicate all the five properties of classical uncouplers listed above (9,15,16

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Isothiocyanates. A new class of uncouplers

Cited by 36 publications

References 21 publications

Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells

Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells

Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action

Mechanism of uncoupling in mitochondria: uncouplers as ionophores for cycling cations and protons.

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