Chemotherapy: targeting the mitochondrial cell death pathway

Debatin, Klaus‐Michael; Poncet, Delphine; Kroemer, Guido

doi:10.1038/sj.onc.1206039

Cited by 362 publications

(257 citation statements)

References 173 publications

(131 reference statements)

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“…In addition, many agents induce cellular stress, which can also lead to mitochondrial perturbation and ultimately cell death. A mechanism causing the mitochondrial dysfunction mentioned previously has been proposed that consists of mitochondrial membrane permeability transition, dissipation of the inner membrane potential, osmotic swelling of the matrix, rupture of the outer mitochondrial membrane, release of cytochrome c and other apoptogenic proteins from the mitochondria, and formation of the caspase-3 activation complex, the apoptosome (Debatin et al, 2002;Newmeyer and Ferguson-Miller, 2003). Permeability transition involves the opening of a PTP.…”

Section: Discussionmentioning

confidence: 99%

“…The PTP is formed in regions of contact between the inner and outer mitochondrial membranes. Prolonged opening of the PTP leads to the previously mentioned effects, exposes cytosol to the contents of the mitochondria, and culminates in cell death (Debatin et al, 2002;Newmeyer and Ferguson-Miller, 2003). Interestingly, mitochondrial permeability transition can lead to both apoptosis and necrosis (Lemasters et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

et al. 2006

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In this study, we performed two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionisation time of fly mass spectrometry to identify the protein(s) associated with the development of oral squamous cell carcinomas (OSCCs) by comparing patterns of OSCC-derived cell lines with normal oral keratinocytes (NOKs), and found that downregulation of ubiquitous mitochondrial creatine kinase (CKMT1) could be a good candidate. Decreased levels of CKMT1 mRNA and protein were detected in all OSCC-derived cell lines examined (n ¼ 9) when compared to those in primary normal oral keratinocytes. Although no sequence variation in the coding region of the CKMT1 gene with the exception of a nonsense mutation in exon 8 was identified in these cell lines, we found a frequent hypermethylation in the CpG island region. CKMT1 expression was restored by experimental demethylation. In addition, when we transfected CKMT1 into the cell lines, they showed an apoptotic phenotype but no invasiveness. In clinical samples, high frequencies of CKMT1 downregulation were detected by immunohistochemistry (19 of 52 (37%)) and quantitative real-time RT -PCR (21 of 50 (42%)). Furthermore, the CKMT1 expression status was significantly correlated with tumour differentiation (Po0.0001). These results suggest that the CKMT1 gene is frequently inactivated during oral carcinogenesis and that an epigenetic mechanism may regulate loss of expression, which may lead to block apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

et al. 2006

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“…3A) and early mitochondrial release of cytochrome C (Fig. 3B), hallmarks of the intrinsic, mitochondria-controlled pathway of apoptosis known to be activated by cellular oxidative stress and various chemotherapeutics [39]. Indeed, TBinduced apoptosis was accompanied by massive ROS production as assessed by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining followed by flow cytometric analysis (Fig.…”

Section: Prc-induced Intracellular Oxidative Stress Loss Of Mitochonmentioning

confidence: 96%

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Wondrak

2007

Free Radical Biology and Medicine

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Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redoxcyclers (PRC) induce selective cancer cell apoptosis by NAD (P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redoxcycling as the mechanism of PRC cytotoxicity, co-incubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC-cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRCinduced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1-inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was nine fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC-bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics.

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“…It is assumed that cancer cells have defects in their apoptosis system (Hanahan and Weinberg, 2000;Green and Evan, 2002). Such resistance to apoptosis may play a role both in the development of cancer and in the resistance to radio-and chemotherapy (Debatin et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

Zantl

Weirich²,

Zall³

et al. 2007

Oncogene

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Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-x L , Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.

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Chemotherapy: targeting the mitochondrial cell death pathway

Cited by 362 publications

References 173 publications

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

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