title: A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer.
abstract: Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jai-Hee
authors: JH
authors: Moon
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jae-Sik
authors: JS
authors: Shin
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Seung-Woo
authors: SW
authors: Hong
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Soo-A
authors: SA
authors: Jung
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Ih-Yeon
authors: IY
authors: Hwang
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jeong Hee
authors: JH
authors: Kim
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Eun Kyoung
authors: EK
authors: Choi
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Seung-Hee
authors: SH
authors: Ha
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jin-Sun
authors: JS
authors: Kim
authors: University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Kyoung-Mok
authors: KM
authors: Kim
authors: University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Dae-Won
authors: DW
authors: Hong
authors: Department of Anatomy, Inje University College of Medicine, Busanjin-ku, Busan, Republic of Korea.
authors: Daejin
authors: D
authors: Kim
authors: Department of Anatomy, Inje University College of Medicine, Busanjin-ku, Busan, Republic of Korea.
authors: Yeong Seok
authors: YS
authors: Kim
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jeong Eun
authors: JE
authors: Kim
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Kyu-Pyo
authors: KP
authors: Kim
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Yong Sang
authors: YS
authors: Hong
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Eun Kyung
authors: EK
authors: Choi
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Jung Shin
authors: JS
authors: Lee
authors: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Maureen
authors: M
authors: Hattersley
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Dong-Hoon
authors: DH
authors: Jin
authors: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
authors: Tae Won
authors: TW
authors: Kim
mesh_terms: D000480:Alkynes / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis; D016923:Cell Death; D004318:Doxycycline / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D000480:Alkynes; D017304:Annexin A5; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C586719:N,N'-(2,2'-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(1-(2-cyclohexyl-2-(2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide); D009842:Oligopeptides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline
keywords: AZD5582; IAP antagonist; Mcl-1; apoptosis; pancreatic cancer cells