Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

Tenev, Tencho; Marani, Michela; McNeish, Iain A.; Lemoine, Nicholas R.

doi:10.1038/sj.cdd.4400808

Cited by 39 publications

(29 citation statements)

References 34 publications

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“…22,23 Previous work from our group has indicated that it is possible to derive ovarian carcinoma cell clones that stably express caspase-3, 25 following transfection with the tricistronic tetracycline -regulatable plasmid, pNRTIS ± caspase-3, and selection by growth in medium containing the neomycin analogue, G418. The level of intrinsic procaspase -3 expression differs in the two cell populations investigated.…”

Section: Discussionmentioning

confidence: 99%

“…27 Fulllength human caspase -3 cDNA was generated by reverse transcriptase polymerase chain reaction ( PCR ) from OVCAR3 cells and cloned as an EcoRI fragment into pNRTIS -33. 25 Plasmid maps are presented in Figure 1a.…”

Section: Construction Of Plasmidsmentioning

confidence: 99%

“…We have previously demonstrated that the expression of pro -caspase-3 alone in ovarian carcinoma cells does not induce apoptosis. 25 However, following adenoviral delivery of the tk gene, there is significantly greater death of ovarian carcinoma cells expressing pro -caspase-3 than of control cells upon exposure to GCV. Transfection of the procaspase -3 ±expressing cells with a control adenovirus that does not encode tk fails to enhance sensitivity to GCV.…”

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confidence: 99%

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Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

et al. 2001

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There is a need to enhance the efficacy of genetic prodrug activation therapy using herpes simplex virus thymidine kinase ( tk ) and ganciclovir ( GCV ) following disappointing results in early clinical trials. tk / GCV has been shown to lead to the activation of caspase -3, a potent executor of apoptosis. We demonstrate that co -expression of pro -caspase -3 with tk / GCV leads to enhanced cell death in ovarian carcinoma cells in vitro. Following transfection with recombinant adenoviral vectors encoding tk, GCV treatment leads to greater cell death in pro -caspase -3 ± expressing clones of SKOV3 and IGROV1 than control cells, as well as more rapid activation of caspase -3 and more rapid cleavage of PARP. Flow cytometry suggests that there is a greater degree of S -phase block in the pro -caspase -3 ± expressing clones than in control cells following treatment with tk / GCV. None of these effects is seen following transfection with a control adenovirus that does not encode tk. The increased cell death, early caspase -3 activation and PARP cleavage, and flow cytometric changes seen in pro -caspase -3 ± expressing cells can be partially inhibited by treatment with benzyloxycarbonyl ± val ± ala ± asp fluoromethylketone, a synthetic caspase inhibitor. Our data suggest that co -expression of procaspase -3 may lead to a significant enhancement of the efficacy of tk / GCV therapy. Cancer Gene Therapy ( 2001 ) 8, 308 ± 319

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Section: Discussionmentioning

confidence: 99%

Section: Construction Of Plasmidsmentioning

confidence: 99%

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confidence: 99%

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Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

et al. 2001

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“…37 These data together with our results support the hypothesis that in cancer cells caspases are continuously activated at minimal levels and kept in frame by IAPs. 60,62,63,17 It is clear that further studies are required to confirm this hypothesis. In conclusion, our data indicate that PIs, by sustaining the levels of the IAPs antagonist Smac/DIABLO, can overcome this distal apoptotic checkpoint and they could be powerful drugs to induce cell death of cancer cells that have accumulated mutations in the apoptosome, both as a single agent or in combination with other antitumor treatments.…”

Section: Discussionmentioning

confidence: 95%

Caspase activation and apoptosis in response to proteasome inhibitors

et al. 2005

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Several studies have indicated that proteasome inhibitors (PIs) are promising anticancer agents. We have discovered that PIs have the unique ability to activate effector caspases through a mitochondrial Bcl-2 inhibitable but caspase-9 independent pathway. Stabilization of released Smac induced by blockade of the proteasome could explain the apoptosome-independent cell death induced by PIs. Infact, Smac/ DIABLO critically supports this PIs-dependent caspase activation. By using a new assay, we confirm that at a single cell level both Smac and PIs can activate caspases in the absence of the apoptosome. Moreover, we have observed two PIs-induced kinetics of caspase activation, with caspase-9 being still required for the rapid caspase activation in response to mitochondrial depolarization, but dispensable for the slow DEVDase activation. In summary, our data indicate that PIs can activate downstream caspases at least in part through Smac/DIABLO stabilization.

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“…25,26 Overexpression or restoration of pro-caspase-3 was able to sensitize ovarian and breast cancer cells to treatment. 27,28 Here, we investigated the expression status of two executioner caspases, caspase-3 and caspase-7, in a panel of primary breast carcinomas and tried to analyze whether or not there is a correlation between expression of pro-and active enzymes, apoptotic index, tumor grade and other clinical or morphological parameters.…”

Section: Introductionmentioning

confidence: 99%

Expression of Caspase-3 and -7 Does Not Correlate with the Extent of Apoptosis in Primary Breast Carcinomas

Grigoriev¹,

Pozharissky²,

Hanson³

et al. 2002

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Association between the rate of apoptosis and expression of the several relevant molecules (Bcl-2, pro-and active caspase-3, and caspase-7) was studied in 61 primary breast carcinomas. The rate of apoptosis detected both morphologically and by the TUNEL assay appeared to be high in 18 (30%), moderate in 14 (23%), and low in 29 (48%) carcinomas. High apoptotic index was strongly associated with advanced tumor grade and estrogen receptor positive (ER+) status but not with other investigated clinical or morphological parameters. Among the molecules studied, only the Bcl-2 protein expression demonstrated strong (inverse) correlation with the apoptotic index (p = 0.032). The data of this expected correlation was served as internal control in the study. Interestingly, high levels of the anti-apoptotic protein Bcl-2 was frequently co-incident with increased expression of pro-apoptotic molecules, such as active caspase-3 (p = 0.004) and caspase-7 (p = 0.001). However, expression of caspase-3 or caspase-7 did not show correlation with the extent of apoptosis or any clinico-morphological features, except overrepresentation of ER+ status in tumors expressing caspase-3 (p = 0.009). Thus, these findings indicate a general dysregulation of spontaneous apoptosis in primary breast tumors.

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Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

Cited by 39 publications

References 34 publications

Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

Caspase activation and apoptosis in response to proteasome inhibitors

Expression of Caspase-3 and -7 Does Not Correlate with the Extent of Apoptosis in Primary Breast Carcinomas

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