Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

Rudner, Justine; Elsaesser, Simon J.; Müller, Arndt-Christian; Belka, Claus; Jendrossek, Verena

doi:10.1016/j.bcp.2009.07.021

Cited by 38 publications

(27 citation statements)

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“…In this regard, Bax-deficient Jurkat cells seem to be entirely dependent on Mcl-1 (20,40,41). The prominent inhibitory action of Bcl-xL and the downregulation of Mcl-1 during DHA-induced apoptosis fit well into the concept that proapoptotic Bak is kept in check by Mcl-1 and Bcl-xL and that apoptosis execution requires abrogation of the inhibitory action of these antiapoptotic Bcl-2 family members (42,43).…”

Section: Discussionmentioning

confidence: 69%

“…Because RNAimediated downregulation of NOXA inhibited DHAinduced apoptosis to some extent, a role of NOXA in DHA-mediated apoptosis can be assumed. This is reminiscent of the role of NOXA and Mcl-1 in the cellular response to the nonsteroidal anti-inflammatory drug celecoxib, histone deacetylase inhibitors, and proteasome inhibitors (20,45). Although the observations that loss of Bak and pretreatment with zVAD-fmk do not prevent the upregulation of NOXA suggest that NOXA upregulation is an upstream event, the exact role of NOXA in DHA-induced apoptosis remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…In Jurkat cells with low endogenous levels of Bcl-xL and Bcl-2, Bak is kept in check by antiapoptotic Mcl-1 (20). As shown in Fig.…”

Section: Role Of Bcl-2 Proteins In Dha-induced Apoptosismentioning

confidence: 96%

“…The caspase-9 dominant-negative (DN) construct was kindly provided by E. Alnemri. Jurkat vector cells (Jurkat vector) as well as clones with cytomegalovirus-dependent constitutive expression of Bcl-xL (Jurkat Bcl-xL) and of wild-type Bcl-2 (Jurkat Bcl-2) were used as previously described (20 (21).…”

Section: Cell Lines and Culturementioning

confidence: 99%

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Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

Handrick

Ontikatze

Bauer

et al. 2010

Molecular Cancer Therapeutics

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The sesquiterpene lactone dihydroartemisinin (DHA), a semisynthetic derivative of the herbal antimalaria drug artemisinin, is cytotoxic to human tumor cells. Treatment of Jurkat T-lymphoma cells with DHA induced a breakdown of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases, and DNA fragmentation indicative of apoptosis induction. Although the absence of FADD or caspase-8 did not alter apoptosis rates in Jurkat cells, overexpression of dominant-negative caspase-9 or of antiapoptotic Bcl-xL or Bcl-2 largely decreased the cytotoxicity of DHA, demonstrating a role of the intrinsic death pathway. The proapoptotic Bcl-2 effector protein Bak and the Bcl-2 homology domain 3-only protein NOXA turned out to be important mediators of DHA-induced apoptosis in Jurkat cells. DHA treatment triggered the expression of NOXA and the activation of Bak. Furthermore, DHA-induced apoptosis was completely abrogated by loss of Bak and largely reduced in cells with siRNA-mediated downregulation of Bak or NOXA. Proapoptotic signaling of DHA also involved the formation of reactive oxygen species and membrane oxidation. Pretreatment with the lipophilic radical scavenger vitamin E or the hydrophilic radical scavengers glutathione and N-acetylcysteine reduced DHA-induced membrane oxidation and apoptosis, respectively. Oxidative changes also occurred in cells with disruption of the mitochondrial death pathway, suggesting a role of reactive oxygen species and oxidative membrane changes in death signaling upstream of the mitochondria. Interestingly, DHA increased the cytotoxic action of ionizing radiation and of the death receptor agonist tumor necrosis factor-related apoptosis-inducing ligand in Jurkat cells, suggesting a potential benefit of DHA in combined treatment strategies. Mol Cancer Ther; 9(9); 2497-510. ©2010 AACR.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

“…In Jurkat cells with low endogenous levels of Bcl-xL and Bcl-2, Bak is kept in check by antiapoptotic Mcl-1 (20). As shown in Fig.…”

Section: Role Of Bcl-2 Proteins In Dha-induced Apoptosismentioning

confidence: 96%

Section: Cell Lines and Culturementioning

confidence: 99%

See 2 more Smart Citations

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

Handrick

Ontikatze

Bauer

et al. 2010

Molecular Cancer Therapeutics

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“…As such, a great deal of effort has been focused on the development of agents that target and inhibit COX-2 activity for use in cancer chemotherapy. Unfortunately, moderate or high therapeutic doses of selective COX-2 inhibitors lead to a variety of gastrointestinal and cardiovascular toxicities, and these adverse effects have greatly limited their clinical use in cancer chemoprevention and treatment [5,6]. Recent studies have shown that combined treatment of NSAIDs with other anticancer agents, such as γ-tocotrienol, resulted in synergistic antiproliferative effects [7].…”

Section: Introductionmentioning

confidence: 98%

COX-2-independent induction of apoptosis by celecoxib and polyamine naphthalimide conjugate mediated by polyamine depression in colorectal cancer cell lines

Xie

Zhang

et al. 2011

Int J Colorectal Dis

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Cancer cell killing by Celecoxib: Reality or just in vitro precipitation‐related artifact?

Sacchetti

2013

J of Cellular Biochemistry

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Among NSAIDs Celecoxib is one of the most efficient in triggering in vitro cancer cell death, and from this perspective has been subject of numerous studies. However, it is still controversial whether this in vitro-observed effect can also occur in vivo and contribute to the antitumor action of the drug. Moreover, besides common agreement on the involvement of COX-independent pathways, the mechanisms underlying Celecoxib toxicity are still unclear. In an attempt to shed light on these mechanisms, I found that cell death only occurs at insoluble concentrations of the drug, and follows irreversible binding and damage of the plasmamembrane by precipitates. This evidence strongly suggests that Celecoxib is devoid of true molecular toxicity. Moreover, since plasma levels reached during therapy are far below the threshold of toxic precipitation, direct cytotoxicity by Celecoxib is unlikely to occur on tumor cells in vivo. Thus the antitumor effect might be only due to COX inhibition, which requires significantly lower levels of the drug. Nonetheless, direct cytotoxicity might not be confined to an in vitro artifact, but contribute to the upper gastrointestinal side effects of Celecoxib. Overall, these findings represent an important basis for further studies on Celecoxib, where true molecular actions of the drug should be discriminated from the precipitate-dependent ones, and the relationship between in vitro and in vivo effects considered at the light of the precipitate-dependent model. Moreover, remarkably, this article indicates a model of critical analysis that can be extended to other poorly soluble drugs.

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Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

Cited by 38 publications

References 50 publications

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

COX-2-independent induction of apoptosis by celecoxib and polyamine naphthalimide conjugate mediated by polyamine depression in colorectal cancer cell lines

Cancer cell killing by Celecoxib: Reality or just in vitro precipitation‐related artifact?

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