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Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress.
Cancer Cell Int. 2020; 20:250.CC

Abstract

Background

Acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have a high relapse rate and poor prognosis. This study aims to explore the underlying mechanism of combining Gilteritinib with ATO at low concentration in the treatment of FLT3-ITD positive leukemias.

Methods

We used both in vitro and in vivo studies to investigate the effects of combination of Gilteritinib with ATO at low concentration on FLT3-ITD positive leukemias, together with the underlying molecular mechanisms of these processes.

Results

Combination of Gilteritinib with ATO showed synergistic effects on inhibiting proliferation, increasing apoptosis and attenuating invasive ability in FLT3-ITD-mutated cells and reducing tumor growth in nude mice. Results of western blot indicated that Gilteritinib increased a 160KD form of FLT3 protein on the surface of cell membrane. Detection of endoplasmic reticulum stress marker protein revealed that IRE1a and its downstream signal phosphorylated JNK were suppressed in Gilteritinib-treated FLT3-ITD positive cells. The downregulation of IRE1a induced by Gilteritinib was reversed with addition of ATO. Knockdown of IRE1a diminished the combinatorial effects of Gilteritinib plus ATO treatment and combination of tunicamycin (an endoplasmic reticulum pathway activator) with Gilteritinib achieved the similar effect as treatment with Gilteritinib plus ATO.

Conclusions

Thus, ATO at low concentration potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK signal pathway, targeting IRE1a to cooperate with Gilteritinib may serve as a new theoretical basis on FLT3-ITD mutant AML treatment.

Authors+Show Affiliations

Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32565734

Citation

Hu, Xiaoli, et al. "Arsenic Trioxide Potentiates Gilteritinib-induced Apoptosis in FLT3-ITD Positive Leukemic Cells Via IRE1a-JNK-mediated Endoplasmic Reticulum Stress." Cancer Cell International, vol. 20, 2020, p. 250.
Hu X, Cai J, Zhu J, et al. Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress. Cancer Cell Int. 2020;20:250.
Hu, X., Cai, J., Zhu, J., Lang, W., Zhong, J., Zhong, H., & Chen, F. (2020). Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress. Cancer Cell International, 20, 250. https://doi.org/10.1186/s12935-020-01341-5
Hu X, et al. Arsenic Trioxide Potentiates Gilteritinib-induced Apoptosis in FLT3-ITD Positive Leukemic Cells Via IRE1a-JNK-mediated Endoplasmic Reticulum Stress. Cancer Cell Int. 2020;20:250. PubMed PMID: 32565734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress. AU - Hu,Xiaoli, AU - Cai,Jiayi, AU - Zhu,Jianyi, AU - Lang,Wenjing, AU - Zhong,Jihua, AU - Zhong,Hua, AU - Chen,Fangyuan, Y1 - 2020/06/17/ PY - 2020/03/03/received PY - 2020/06/12/accepted PY - 2020/6/23/entrez PY - 2020/6/23/pubmed PY - 2020/6/23/medline KW - ATO KW - Endoplasmic reticulum stress KW - FLT3-ITD KW - Gilteritinib KW - IRE1a-JNK SP - 250 EP - 250 JF - Cancer cell international JO - Cancer Cell Int. VL - 20 N2 - Background: Acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have a high relapse rate and poor prognosis. This study aims to explore the underlying mechanism of combining Gilteritinib with ATO at low concentration in the treatment of FLT3-ITD positive leukemias. Methods: We used both in vitro and in vivo studies to investigate the effects of combination of Gilteritinib with ATO at low concentration on FLT3-ITD positive leukemias, together with the underlying molecular mechanisms of these processes. Results: Combination of Gilteritinib with ATO showed synergistic effects on inhibiting proliferation, increasing apoptosis and attenuating invasive ability in FLT3-ITD-mutated cells and reducing tumor growth in nude mice. Results of western blot indicated that Gilteritinib increased a 160KD form of FLT3 protein on the surface of cell membrane. Detection of endoplasmic reticulum stress marker protein revealed that IRE1a and its downstream signal phosphorylated JNK were suppressed in Gilteritinib-treated FLT3-ITD positive cells. The downregulation of IRE1a induced by Gilteritinib was reversed with addition of ATO. Knockdown of IRE1a diminished the combinatorial effects of Gilteritinib plus ATO treatment and combination of tunicamycin (an endoplasmic reticulum pathway activator) with Gilteritinib achieved the similar effect as treatment with Gilteritinib plus ATO. Conclusions: Thus, ATO at low concentration potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK signal pathway, targeting IRE1a to cooperate with Gilteritinib may serve as a new theoretical basis on FLT3-ITD mutant AML treatment. SN - 1475-2867 UR - https://www.unboundmedicine.com/medline/citation/32565734/Arsenic_trioxide_potentiates_Gilteritinib-induced_apoptosis_in_FLT3-ITD_positive_leukemic_cells_via_IRE1a-JNK-mediated_endoplasmic_reticulum_stress L2 - https://cancerci.biomedcentral.com/articles/10.1186/s12935-020-01341-5 DB - PRIME DP - Unbound Medicine ER -
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