Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

Trauzold, Anna; Schmiedel, Stefan; Röder, Christian; Tams, C.; Christgen, Matthias; Oestern, Stefanie; Arlt, Alexander; Westphal, Sabine; Kapischke, Matthias; Ungefroren, Hendrik; Kalthoff, Holger

doi:10.1038/sj.bjc.6601330

Cited by 66 publications

(55 citation statements)

References 37 publications

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“…We show here that XIAP is overexpressed in the majority of human pancreatic cancers, as assessed by immunohistochemistry, confirming for the first time data that have been reported previously only in cell line models (13,14). Although the numbers of cases analyzed are relatively small, the trend clearly underscores that XIAP up-regulation is a common phenomenon in pancreatic cancer.…”

Section: Discussionsupporting

confidence: 74%

“…Because many therapeutic modalities principally act by promoting apoptosis, alterations in this intracellular cascade can render neoplastic cancer cells resistant to therapy (6). A family of endogenous antiapoptotic proteins known as inhibitors of apoptosis proteins (IAP), which bind and repress proapoptotic caspases in their quiescent 'zymogen' state, is frequently overexpressed in both solid and hematologic malignancies (7 -12), including pancreatic cancer (13,14). It is postulated that IAPs may be a major cause of the resistance to chemoradiation therapy -induced apoptosis observed in neoplastic cells; therefore, blockade of IAP function while simultaneously initiating cellular apoptosis would have the effect of overcoming this resistance state (15,16).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Karikari¹,

Roy²,

Tryggestad

et al. 2007

Molecular Cancer Therapeutics

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Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (''XAntag''; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC 50 in the range of 2 to 5 Mmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream ''effector'' caspases (caspase-3 and caspase-7) versus the upstream ''initiator'' caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957 -66]

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Karikari¹,

Roy²,

Tryggestad

et al. 2007

Molecular Cancer Therapeutics

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“…In some pancreatic carcinoma cell lines, we observed a slight increase in cell viability upon treatment with low concentrations of TRAIL (Figure 1b) in line with our previous findings that TRAIL may trigger proliferation under certain circumstances (Ehrhardt et al, 2003). Based on these studies, we selected PaTuII, PancTu1, ASPC1 and DanG pancreatic carcinoma cells, which were relatively resistant towards TRAIL, and Colo357 as a prototype TRAIL-sensitive cell line to identify molecular (Hinz et al, 2000;Trauzold et al, 2003). This indicates that resistance to TRAIL is presumably caused by mechanisms acting further downstream in the TRAIL signaling pathway.…”

Section: Trail-induced Cell Death In Pancreatic Carcinoma Cellssupporting

confidence: 53%

Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells

et al. 2006

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy because of its relative tumor selectivity. However, many cancers including pancreatic cancer remain resistant towards TRAIL. To develop TRAIL for cancer therapy of pancreatic carcinoma, it will therefore be pivotal to elucidate the molecular mechanisms of TRAIL resistance. Here, we identify X-linked inhibitor of apoptosis (XIAP) as a regulator of TRAIL sensitivity in pancreatic carcinoma cells. Full activation of effector caspases, loss of mitochondrial membrane potential and cytochrome c release following TRAIL treatment were markedly impaired in pancreatic carcinoma cell lines, which poorly responded to TRAIL (PaTuII, PancTu1, ASPC1, DanG), compared to TRAIL-sensitive Colo357 pancreatic carcinoma cells. Stable downregulation of XIAP by RNA interference significantly reduced survival and enhanced TRAIL-induced apoptosis in pancreatic carcinoma cells. Also, downregulation of XIAP significantly increased CD95-induced cell death. Importantly, knockdown of XIAP strongly inhibited clonogenicity of pancreatic cancer cells treated with TRAIL indicating that XIAP promotes clonogenic survival of pancreatic carcinoma cells. Thus, our findings for the first time indicate that targeting XIAP represents a promising strategy to enhance the antitumor activity of TRAIL in pancreatic cancer, which has important clinical implications.

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“…The reason for this spectrum of response to TRAIL-R activation is due to the complex downstream regulation of the cell death pathway. Intracellular levels of pro-and antiapoptotic factors such as cFLIP (Kim et al, 2000;Sayers et al, 2003), XIAP Chawla-Sarkar et al, 2002), BCL-2 family members (Burns and El-Deiry, 2001;LeBlanc et al, 2002), and DISC formation and caspase 8 activity (Trauzold et al, 2003) have been reported to regulate cell sensitivity to TRAIL-induced programmed cell death in both tumour and normal cells. Although TRAIL decoy receptors have been implicated in the regulation of TRAIL signalling, the presence of decoy receptors (DcR1, DcR2) are not a factor in resistance to HGS-ETR1 activity, as HGS-ETR1 does not bind to either of these receptors (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

et al. 2005

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

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Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

Cited by 66 publications

References 37 publications

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

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