The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia

被引：27

作者：

Espinoza, J. Luis ^{[1
]}

Elbadry, Mahmoud I. ^{[1
,6
]}

Taniwaki, Masafumi ^{[2
]}

Harada, Kenichi ^{[3
]}

Ly Quoc Trung ^{[1
]}

Nakagawa, Noriharu ^{[1
]}

Takami, Akiyoshi ^{[4
]}

Ishiyama, Ken ^{[1
]}

Yamauchi, Takuji ^{[5
]}

Takenaka, Katsuto ^{[5
]}

Nakao, Shinji ^{[1
]}

机构：

[1] Kanazawa Univ, Grad Sch Med Sci, Dept Hematol & Oncol, Takara Machi 13-1, Kanazawa, Ishikawa, Japan

[2] Kyoto Prefectural Univ Med, Ctr Mol Diagnost & Therapeut, Kamigyo Ku, Kawaramachi Hirokoji, Kyoto 6028566, Japan

[3] Kanazawa Univ, Grad Sch Med Sci, Dept Human Pathol, Takara Machi 13-1, Kanazawa, Ishikawa 9208640, Japan

[4] Aichi Med Univ, Sch Med, Dept Internal Med, Div Hematol, 1-1 Yazakokarimata, Nagakute, Aichi 4801195, Japan

[5] Kyushu Univ, Grad Sch Med Sci, Dept Med & Biosyst Sci, Fukuoka, Japan

[6] Sohag Univ Hosp, Fac Med, Dept Internal Med, Div Hematol, Sohag, Egypt

来源：

CANCER LETTERS | 2017年 / 400卷

基金：

日本学术振兴会;

关键词：

Stilbenoid; Monosomal karyotype leukemia; Gnetin-C; Apoptosis; Cell signaling; ACUTE MYELOGENOUS LEUKEMIA; MONOSOMAL KARYOTYPE; MEK INHIBITION; GNEMON L; CELLS; ACTIVATION; COMPLEX; STRATEGIES; RESISTANCE; MUTATIONS;

D O I：

10.1016/j.canlet.2017.04.027

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Acute myelogenous leukemia (AML) is a clinically heterogeneous disease that is frequently associated with relapse and a poor prognosis. Among the various subtypes, AML with the monosomal karyotype (AML-MK) has an extremely unfavorable prognosis. We performed screening to identify antitumor compounds that are capable of inducing apoptosis in primary leukemia cells harboring the AML-MK karyotype and identified a naturally occurring stilbene, Gnetin-C, with potent anti-tumor activities against AML cells from patients with various cytogenetic abnormalities, including patients with the AML-MK karyotype. Gnetin-C simultaneously inhibits the ERK1/2 and the AKT/mTOR pathways, two signals that are essential for the survival of leukemia cells. A combination of Gnetin-C with low doses of chemotherapeutic drugs led to synergistic anti-tumor effects against AML cells. In an immunodeficient mouse model of human leukemia, Gnetin-C attenuated the formation of leukemia, depleted leukemia cells and improved survival. These findings suggest that Gnetin-C has antitumor activities in AML and supports the therapeutic potential of blocking two different pathways in AML. (C) 2017 Elsevier B.V. All rights reserved.

引用

页码：127 / 136

页数：10

共 37 条

[1] Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rγ null mice generate a faster and more efficient disease compared to other NOD/scid-related strains [J].

Agliano, Alice ;

Martin-Padura, Ines ;

Mancuso, Patrizia ;

Marighetti, Paola ;

Rabascio, Cristina ;

Pruneri, Giancarlo ;

Shultz, Leonard D. ;

Bertolini, Francesco .

INTERNATIONAL JOURNAL OF CANCER, 2008, 123 (09) :2222-2227

[2]

Aluyen Julia Khristine, 2012, Journal of Dietary Supplements, V9, P45, DOI 10.3109/19390211.2011.650842

[3] mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology [J].

Betz, Charles ;

Stracka, Daniele ;

Prescianotto-Baschong, Cristina ;

Frieden, Maud ;

Demaurex, Nicolas ;

Hall, Michael N. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (31) :12526-12534

[4] Monosomal karyotype in acute myeloid leukemia:: A better indicator of poor prognosis than a complex karyotype [J].

Breems, Dimitri A. ;

Van Putten, Wim L. J. ;

De Greef, Georgine E. ;

Van Zelderen-Bhola, Shama L. ;

Gerssen-Schoorl, Klasien B. J. ;

Mellink, Clemens H. M. ;

Nieuwint, Aggie ;

Jotterand, Martine ;

Hagemeijer, Anne ;

Beverloo, H. Berna ;

Lowenberg, Bob .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (29) :4791-4797

[5] Preclinical efficacy of MEK inhibition in Nras-mutant AML [J].

Burgess, Michael R. ;

Hwang, Eugene ;

Firestone, Ari J. ;

Huang, Tannie ;

Xu, Jin ;

Zuber, Johannes ;

Bohin, Natacha ;

Wen, Tiffany ;

Kogan, Scott C. ;

Haigis, Kevin M. ;

Sampath, Deepak ;

Lowe, Scott ;

Shannon, Kevin ;

Li, Qing .

BLOOD, 2014, 124 (26) :3947-3955

[6] Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases [J].

Cargnello, Marie ;

Roux, Philippe P. .

MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, 2011, 75 (01) :50-83

[7] Targeting the mTOR Pathway in Leukemia [J].

Dinner, Shira ;

Platanias, Leonidas C. .

JOURNAL OF CELLULAR BIOCHEMISTRY, 2016, 117 (08) :1745-1752

[8] The myth of the second remission of acute leukemia in the adult [J].

Forman, Stephen J. ;

Rowe, Jacob M. .

BLOOD, 2013, 121 (07) :1077-1082

[9]

Fransecky Lars, 2015, Mol Cell Ther, V3, P2

[10]

FURUKAWA T, 1994, LEUKEMIA, V8, P171

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