Cisplatin Induces the Proapoptotic Conformation of Bak in a ΔMEKK1-Dependent Manner

Mandic, Aleksandra; Viktorsson, Kristina; Molin, Magnus; Akusjärvi, Göran; Eguchi, Hidetaka; Hayashi, Shin Ichi; Toi, Masakazu; Hansson, Johan; Linder, Stig; Shoshan, Maria C.

doi:10.1128/mcb.21.11.3684-3691.2001

Cited by 71 publications

(74 citation statements)

References 34 publications

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“…These results suggest that the combination treatment enhances mitochondrial activation -mediated apoptotic cell death in U937 cells. In response to certain stimuli that require mitochondria-dependent pathway for apoptosis, Bax become activated, translocated to the outer membrane of mitochondria, and oligomerized therein (42). The mitochondrial membrane potential loss and the release of mitochondrial apoptogenic molecules into the cytosol ensue.…”

Section: Discussionmentioning

confidence: 99%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

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Section: Discussionmentioning

confidence: 99%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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“…A variety of apoptotic stimuli, including DNA damaging agents and oxidative stress, have been reported to stimulate the intrinsic mitochondrial apoptotic pathway by activating, and upregulating, pro-apoptotic Bcl-2 family proteins (Bax and Bak), thereby provoking dissipation of the mitochondrial trans-membrane potential (Mandic et al, 2001;Jungas et al, 2002;Panaretakis et al, 2002;Chada et al, 2006;Donahue et al, 2006;Kuhar et al, 2006;Zhang et al, 2006;Baysan et al, 2007;Jantova et al, 2007). Our observations of Bax and Bak activation and up-regulation, together with attenuation of mitochondrial trans-membrane potential in lymphoblasts undergoing DEB-induced apoptosis, are in line with these reports.…”

Section: Discussionmentioning

confidence: 99%

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Yadavilli¹,

Martinez‐Ceballos²,

Snowden-Aikens³

et al. 2007

Toxicology in Vitro

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Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1, 3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat-T lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells.Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.

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“…Cisplatin induces apoptosis in 224 and HCT116 cells within 24 hr, as evidenced by loss of mitochondrial membrane permeabilization, activation of BAK, Annexin V positivity and activation of caspases 18,22 ; data not shown. The dose-response and time kinetics for accumulation of caspase-cleaved fragments of cytokeratin-18 in HCT116 cell cultures (cells 1 medium) are shown in Figure 2a.…”

Section: Cisplatin Induces Increases In Ca 21mentioning

confidence: 99%

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Berndtsson

Hägg

Panaretakis

et al. 2006

Intl Journal of Cancer

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197

162

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Cisplatin is a broad-spectrum anticancer drug that is also widely used in experimental studies on DNA damage-induced apoptosis. Induction of apoptosis within 24-48 hr requires cisplatin concentrations that are at least one order of magnitude higher than the IC 50 . Here, we show that such high, apoptosis-inducing cisplatin concentrations induce cellular superoxide formation and that apoptosis is inhibited by superoxide scavengers. The same concentration limit and the requirement for superoxide are also true for induction of caspase activation in enucleated cells (cytoplasts), showing that cisplatin-induced apoptosis occurs independently of nuclear DNA damage. In contrast, lower cisplatin concentrations, which do not induce acute apoptosis, are sufficient for induction of DNA damage signaling. We propose that the antiproliferative effects of cisplatin at IC 50 doses involve premature senescence and secondary, nonstress-induced apoptosis. The higher doses currently used in in vitro studies lead to acute, stress-induced apoptosis that involves induction of superoxide but is largely DNA damage-independent. ' 2006 Wiley-Liss, Inc.Key words: cisplatin; DNA damage; apoptosis; senescence Cis-diamminedichloroplatinum (II) (cisplatin) is a commonly used anticancer agent, especially effective in the treatment of testicular carcinoma and also used to treat other malignancies such as ovarian, cervix, head-and-neck and small-cell lung cancer. 1 Cisplatin forms covalent bonds to the N7 positions of DNA purines to form intra-or interstrand crosslinks, and DNA is generally acknowledged as the primary target of cisplatin. 2,3 Cisplatin is a commonly used model agent for induction of DNA damage-dependent apoptosis in vitro. Acute apoptosis is induced within 24-36 hr, and major efforts have been performed to elucidate apoptotic signaling pathways induced by cisplatin within this time frame. These various studies have highlighted the roles of c-ABL, stressactivated protein kinases and p53 as downstream mediators of cisplatin-induced DNA damage and as mediators of apoptotic signaling (recently reviewed in 3 ). In addition to induction of apoptosis, cisplatin also induces premature senescence. 4 Premature senescence is currently thought to be related to replicative senescence, which has been demonstrated to be a DNA damage response. 5 During replicative senescence, signaling pathways involving ATM (Ataxia telangiectasia mutated) and p53 are activated by telomere uncapping. 5,6 The same signaling mechanisms are believed to be involved in premature senescence induced by DNA damaging drugs. 6,7 Apoptosis and senescence are obviously mutually exclusive cellular outcomes. The factors that decide whether cisplatin will trigger apoptosis or senescence are not clearly understood. In one scenario, senescence and apoptosis represent graded responses to increasing DNA damage. In more complex scenarios, cisplatin induces senescence and apoptosis by different (or partially different) mechanisms.As inducer of apoptosis, cisplatin is used at very d...

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Cisplatin Induces the Proapoptotic Conformation of Bak in a ΔMEKK1-Dependent Manner

Cited by 71 publications

References 34 publications

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

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