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

Moon, Jai‐Hee; Shin, Jae‐Sik; Sheng, Hong; Jung, Sun Young; Hwang, In-Sun; Kim, Jeong Hee; Choi, Eun Kyoung; Ha, Seung-Hee; Kim, Jin-Sun; Kim, Kyoung-Mok; Hong, Dae-Won; Kim, Daejin; Kim, Yeong Seok; Kim, Jeong Eun; Kim, Kyu-Pyo; Hong, Yong Sang; Choi, Eun Kyung; Lee, Jung Shin; Hattersley, Maureen M.; Jin, Dayong; Kim, Tae Won

doi:10.18632/oncotarget.4822

Cited by 23 publications

(15 citation statements)

References 26 publications

(30 reference statements)

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“…Our top goal in this study was to find out whether FL118 alone or in combination with common pancreatic cancer chemotherapeutic drugs used in the clinic could overcome treatment-resistance in pancreatic cancer. The basis for this potential, and the initiation of this study is that upregulation of antiapoptotic proteins, survivin [ 31 – 38 ], Mcl-1 [ 39 – 47 ], XIAP [ 35 , 36 , 38 , 44 , 48 – 55 ], and cIPA2 [ 55 ] are strongly involved in pancreatic cancer resistance, and that FL118 has been found to inhibit such gene expression in CRC and head-&-neck tumors [ 9 ]. Based on the known mechanisms of action (MOA) and other characteristics of FL118 [ 9 ], we first determined the effects of FL118 on the expression of both antiapoptotic and proapoptotic proteins in drug-resistant pancreatic cancer cells (PANC1, MIA PaCa-2).…”

Section: Discussionmentioning

confidence: 99%

“…This result suggests that FL118 may have high efficacy to inhibit both tumor cell proliferation and latent cancer stem cells for effectively eliminating pancreatic cancer in the condition more closely to the clinical practice situation. This is highly possible, because survivin [ 31 – 38 ], Mcl-1 [ 39 – 47 ], XIAP [ 35 , 36 , 38 , 44 , 48 – 55 ], and cIPA2 [ 55 ] play critical roles in pancreatic cancer resistance to treatment, and it is also known that survivin [ 56 – 69 ], Mcl-1 [ 70 , 71 ] and XIAP [ 54 ] are involved in latent CSC drug resistance and function. Furthermore, it is well documented that ABCG2 as a critical efflux pump protein plays a vital role in maintaining viability of latent stem-like cancer cells [ 23 – 29 ], and the increase of ABCG2 [ 13 – 17 ], Pgp [ 18 – 21 ] expression is important for pancreatic cancer resistance to commonly used pancreatic cancer drugs in the clinic.…”

Section: Discussionmentioning

confidence: 99%

“…These findings are consistent with our observations that FL118 inhibits multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and critical DNA repair regulators such as ERCC6 in drug resistant pancreatic cancer cells. It is known that survivin [ 31 – 38 ], Mcl-1 [ 39 – 47 ], XIAP [ 35 , 36 , 38 , 44 , 48 – 55 ], and cIPA2 [ 55 ] are strongly involved in treatment resistance of PDAC; survivin [ 56 – 69 ] and Mcl-1 [ 70 , 71 ] play important roles in cancer stem cell (CSC) drug resistance and function. ERCC6 is important for active gene repair [ 72 ], correcting transcription-coupled DNA repair defects [ 73 ] and being involved in drug resistance [ 74 ].…”

Section: Introductionmentioning

confidence: 99%

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An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer

Ling

Fan

et al. 2018

J Exp Clin Cancer Res

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BackgroundPancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic.MethodsThis study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118’s efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs.ResultsOur studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities.ConclusionTogether, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer

Ling

Fan

et al. 2018

J Exp Clin Cancer Res

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“…Moon et al have shown that the novel small-molecule ZAD5582 promoted TNF-α-induced apoptosis through targeting cIAP1 and XIAP in human pancreatic cancer cells [ 156 ]. AEG35156, a novel second-generation antisense oligonucleotide directed towards XIAP, increased sensitization of pancreatic carcinoma cells to TRAIL–mediated apoptosis as a single agent and was capable of inducing complete tumor regression when combined with taxanes in three human cancer xenograft models (prostate, colon, and lung) [ 157 ].…”

Section: Anti-apoptotic Mechanisms In Resistance To Chemotherapymentioning

confidence: 99%

Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Alimbetov

Askarova

Umbayev

et al. 2018

IJMS

118

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Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment.

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“…The inhibitors of the apoptosis protein (IAP) family, which is characterized by 1–3 copies of Baculoviral IAP Repeat (BIR) domain, has been proved to play functional roles in cancer cell apoptosis [ 5 – 7 ]. High levels of IAP are observed in various cancers, such as glioblastoma and pancreatic cancer [ 8 , 9 ]. It has been reported that the IAP family can regulate cell survival via binding to the pro-apoptotic factors in tumors [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Baculoviral IAP Repeat Containing 6 (BIRC6) Is a Predictor of Prognosis in Prostate Cancer

Zhuang¹,

Zhang²,

Hao³

et al. 2018

Med Sci Monit

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BackgroundBaculoviral IAP repeat containing 6 (BIRC6), a member of the inhibitors of apoptosis protein (IAP) family, has been reported to be correlated with oncogenesis. The aim of this study was to investigate the prognostic significance of BIRC6 in prostate cancer, as well as its effects on prostate cancer cell lines.Material/MethodsBIRC6 protein expression was investigated in 112 prostate cancer tissues and 86 benign prostate disease tissues using immunohistochemistry. Overall survival was assessed by Kaplan-Meier analysis with log-rank test. To evaluate the prognostic significance of BIRC6, Cox regression models were applied. The effects of BIRC6 on human prostate cancer cells were confirmed via small interfering RNA.ResultsBIRC6 protein levels were significantly higher in prostate cancer tissues than that in benign prostate tissues (P<0.001). High BIRC6 expression was associated with advanced pathological stage (P=0.011) and positive metastasis (P=0.036). In addition, patients with high BIRC6 expression had worse survival than those with low expression (Log-rank test, P=0.002). Multivariate analysis demonstrated that BIRC6 expression was an independent prognostic factor for prostate cancer (HR=2.771, 95%CI=1.427–5.378, P=0.003). Furthermore, cell experiments suggested that BIRC6 knockdown inhibits cell proliferation and promote apoptosis (P<0.05 for all).ConclusionsUpregulated BIRC6 predicts aggressive clinical characteristics and poor prognosis in prostate cancer patients. BIRC6 can regulate prostate cancer cell proliferation and apoptosis, which may be a potential therapeutic target.

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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: ABSTRACT

Cited by 23 publications

References 26 publications

An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer

An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer

Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells

Baculoviral IAP Repeat Containing 6 (BIRC6) Is a Predictor of Prognosis in Prostate Cancer

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