Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

Kuroda, Junya; Kimura, Shinya; Strasser, Andreas; Andreeff, Michael; O’Reilly, Lorraine A.; Ashihara, Eishi; Kamitsuji, Yuri; Yokota, Asumi; Kawata, Eri; Takeuchi, Miki; Tanaka, Ray; Tabe, Yoko; Taniwaki, Masafumi; Maekawa, Taira

doi:10.1038/sj.cdd.4402168

Cited by 62 publications

(42 citation statements)

References 41 publications

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“…Bim, a proapoptotic Bcl-2 homology 3-only protein (36), is elevated after ablation of Bcr-Abl and epidermal growth factor receptor signaling (37)(38)(39). However, our data showed that the levels of Bim were unperturbed after HHT treatment (Figs.…”

Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrcontrasting

confidence: 54%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KITelicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211-23. ©2010 AACR.

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Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrcontrasting

confidence: 54%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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“…As previously reported, INNO-406 shuts down Bcr-Abl and upregulates several BH3-only proteins, such as Bim, Bad, Bmf and Bik, 32 followed by MOMP, which is known as 'the point of no-return' for cell death commitment. 10,33 As INNO-406 inhibits Bcr-Abl signaling as imatinib does, these events probably occur through shutdown of the downstream of Bcr-Abl signaling pathway, signal transducer and activator of transcription and phosphoinositide-3-kinase (PI3K)/Akt pathways.…”

Section: Discussionmentioning

confidence: 71%

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

et al. 2008

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Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl þ ) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspaseindependent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl þ leukemias.

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“…IM induces apoptosis through the activation of Bim and Bad, BH3-only proteins (1,2). In this context, Bim inhibits all antiapoptotic Bcl-2 proteins, that is, Bcl-2, Bcl-X L and Mcl-1, whereas Bad inhibits only Bcl-2 and Bcl-X L , but not Mcl-1 (20,21,32).…”

Section: Discussionmentioning

confidence: 99%

“…The constitutive active fusion tyrosine kinase (TK) Bcr-Abl is responsible for deregulated cell proliferation and resistance to cytotoxic insults in chronic myelogenous leukemia (CML) cells, whereas the blockade of the BcrAbl signaling pathway by TK inhibitors (TKI) leads to the inhibition of cell proliferation and induces apoptosis mediated by Bim, a proapoptotic BH3-only protein, in CML cells (1)(2)(3). TKIs against Bcr-Abl such as imatinib mesylate (IM) have greatly improved the therapeutic outcome of CML patients, but treatment failure by resistance or intolerance to IM may occur in ∼40% of patients with CML in the chronic phase (4), and even the more potent second generation Bcr-Abl TKIs, such as nilotinib and dasatinib, are not always promising for IM-refractory CML (5,6).…”

Section: Introductionmentioning

confidence: 99%

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Kuroda

Yamamoto

Nagoshi

et al. 2010

Molecular Cancer Research

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Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC 50 s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/ cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl T315I , or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines.

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Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

Cited by 62 publications

References 41 publications

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

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