Mitochondria: A novel target for the chemoprevention of cancer

Hail, Numsen

doi:10.1007/s10495-005-0792-8

Cited by 100 publications

(104 citation statements)

References 241 publications

(235 reference statements)

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“…Although anti-cancer drugs have been described that may target the UbQ sites on the oxidoreductase complexes along the mitochondrial respiratory chain to increase cellular ROS levels and activate apoptosis (Dias and Bailly, 2005;Hall, 2005;Le et al, 2007), a-TOS has an additional feature in that it also disrupts the anti-apoptotic function of Bcl-2 and Bcl-x L by blocking their BH3-binding domain (Shiau et al, 2006). Hence, a-TOS may prove superior for inducing cancer cell death because of its dual action on two important targets, Q P and Q D sites of CII, and the Bcl-2 family proteins, promoting the induction of mitochondrially mediated apoptosis.…”

Section: Complex II As An Anti-cancer Drug Target L-f Dong Et Almentioning

confidence: 99%

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

et al. 2008

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a-Tocopheryl succinate (a-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of a-TOS has not been identified. Here, we show that a-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of a-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of a-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to a-TOS. We propose that a-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

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Section: Complex II As An Anti-cancer Drug Target L-f Dong Et Almentioning

confidence: 99%

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

et al. 2008

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“…The dysregulation of cellular apoptotic processes is closely associated with tumor development, and the mitochondria are the central organelles that orchestrate apoptosis (Li et al, 2004;Hail, 2005). The Bcl-2 family of proteins comprises subfamilies of pro-survival and pro-apoptotic members.…”

Section: Introductionmentioning

confidence: 99%

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

et al. 2010

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Some mutations in FOXL2 result in premature ovarian failure accompanied by blepharophimosis, ptosis, epicanthus inversus syndrome type I disease, and FOXL2-null mice exhibit developmental defects in granulosa cells. Recently, FOXL2 c.402C4G, a new somatic mutation that leads to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell tumors (GCTs). In this study, we investigated the possible mechanisms by which the C134W mutation contributes to the development of GCTs. Wild-type (WT) and mutant FOXL2 displayed differential apoptotic activities. Specifically, WT FOXL2 induced significant granulosa cell death, but the mutant exhibited minimal cell death. The FOXL2-induced apoptotic response was greatly dependent on caspase 8, BID and BAK because the depletion of any of these three proteins inhibited FOXL2 from eliciting the full apoptotic response. Activation of caspase 8 and subsequent increased production of truncated BID, and oligomerization of BAK, and release of cytochrome c were all associated with the apoptosis induced by WT FOXL2 expression. In contrast, the mutant FOXL2 was unable to elicit the full array of apoptotic signaling responses. In addition, we found differential TNF-R1 (tumor necrosis factor-receptor 1) and Fas (CD95/APO-1) upregulation between the WT and the mutant, and the silencing of TNF-R1 or Fas and the blockage of the death signaling mediated by TNF-R1 or Fas using TNF-Fc or Fas-Fc, respectively, resulted in significant attenuations of FOXL2-induced apoptosis. Moreover, granulosa cells that expressed either WT FOXL2 or mutant exhibited distinct cell death sensitivities on activation of death receptors and deprivation of serum. Thus, the differential activities of FOXL2 and its mutant may partially account for the pathophysiology of GCT development.

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“…12 Mitochondria have a central role as the garden of cell death, which regulates mitochondrial membrane potential (DeltaPsim) and mitochondrial outer membrane permeabilization (MOMP). 13,14 Chemotherapeutic druginduced decrease in DeltaPsim leads to an increase in MOMP, resulting in the release of proapoptotic small molecules such as cytochrome c, second mitochondriaderived activator of caspase/direct inhibitor of apoptosisbinding protein with low pl (Smac/DIABLO) and apoptosis-inducing factor (AIF) through permeability transition pores in caspase-dependent and -independent pathways. 15,16 Chemotherapeutic drug-induced MOMP promotes Bax/Bak oligomerization and their translocation to mitochondrial membranes, which induces the release of proapoptotic molecules from the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

et al. 2006

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Bcl-2 is an oncoprotein that plays a critical role in inhibiting apoptotic cell death in the mitochondria-dependent pathway in cancer chemotherapy. As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors. Although several preclinical and clinical studies have shown the therapeutic efficacy of Bcl-2 in combination with an anticancer drug as a chemosensitizer, in clinical trials the downregulation of Bcl-2 has not been observed with a high frequency in tumor cells. Nevertheless, previous studies showed nonantisense effects such as production of reactive oxygen species and immunostimulatory action through cytosine-phosphate-guanosine-motif in the antisense oligodeoxynucleotides. Further, Bcl-2 is able to inhibit Beclin 1-dependent autophagic cell death, which is a nonapoptotic cell death. The current status and future directions of AS Bcl-2 and the potential mechanisms for multiple roles that Bcl-2 has in cancer therapy are reviewed.

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Mitochondria: A novel target for the chemoprevention of cancer

Cited by 100 publications

References 241 publications

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

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

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

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