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

J. Luis Espinoza, Mahmoud I. Elbadry, Masafumi Taniwaki, Kenichi Harada, Ly Quoc Trung, Noriharu Nakagawa, Akiyoshi Takami, Ken Ishiyama, Takuji Yamauchi, Katsuto Takenaka, Shinji Nakao

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Abstract

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.

Original languageEnglish
Pages (from-to)127-136
Number of pages10
JournalCancer Letters
Volume400
DOIs
Publication statusPublished - Aug 1 2017

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Acute Myeloid Leukemia
Apoptosis
Leukemia
Karyotype
Cell Survival
Stilbenes
gnetin C
Chromosome Aberrations
Signal Transduction
Neoplasms
Recurrence
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Espinoza, J. L., Elbadry, M. I., Taniwaki, M., Harada, K., Trung, L. Q., Nakagawa, N., ... Nakao, S. (2017). The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia. Cancer Letters, 400, 127-136. https://doi.org/10.1016/j.canlet.2017.04.027

The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia. / Espinoza, J. Luis; Elbadry, Mahmoud I.; Taniwaki, Masafumi; Harada, Kenichi; Trung, Ly Quoc; Nakagawa, Noriharu; Takami, Akiyoshi; Ishiyama, Ken; Yamauchi, Takuji; Takenaka, Katsuto; Nakao, Shinji.

In: Cancer Letters, Vol. 400, 01.08.2017, p. 127-136.

Research output: Contribution to journalArticle

Espinoza, JL, Elbadry, MI, Taniwaki, M, Harada, K, Trung, LQ, Nakagawa, N, Takami, A, Ishiyama, K, Yamauchi, T, Takenaka, K & Nakao, S 2017, 'The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia', Cancer Letters, vol. 400, pp. 127-136. https://doi.org/10.1016/j.canlet.2017.04.027
Espinoza, J. Luis ; Elbadry, Mahmoud I. ; Taniwaki, Masafumi ; Harada, Kenichi ; Trung, Ly Quoc ; Nakagawa, Noriharu ; Takami, Akiyoshi ; Ishiyama, Ken ; Yamauchi, Takuji ; Takenaka, Katsuto ; Nakao, Shinji. / The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia. In: Cancer Letters. 2017 ; Vol. 400. pp. 127-136.
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