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The molecular mechanism of a novel derivative of BTO-956 induced apoptosis in human myelomonocytic lymphoma cells

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Abstract

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.

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All data generated or analysed during this study are included in this published article [and its supplementary information files].

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Author notes

  1. Yu-Lin Li and De-Jun Zhou have contributed equally.

Authors and Affiliations

  1. Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Yu-Lin Li, Qian-Wen Feng & Hidekuni Inadera

  2. Graduate School of Medicine, Henan Polytechnic University, Jiaozuo, 454000, China

    De-Jun Zhou

  3. Department of Environmental Health, University of Fukui School of Medical Sciences, 23-3 Matsuoka Shimoaizuki Eiheiji, Fukui, 910-1193, Japan

    Zheng-Guo Cui & Yusuke Hiraku

  4. Department of Pediatric Cardiology, Heart Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, China

    Lu Sun

  5. Department of Public Health and Nutrition, The University of Haripur, Hattar Road, Haripur, KP, Pakistan

    Shahbaz Ahmad Zakki

  6. Department of Molecular Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Xicheng District Xinjiekou East Street on the 31st, Beijing, 100035, China

    Cheng-Ai Wu

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  1. Yu-Lin Li
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Li, YL., Zhou, DJ., Cui, ZG. et al. The molecular mechanism of a novel derivative of BTO-956 induced apoptosis in human myelomonocytic lymphoma cells. Apoptosis 26, 219–231 (2021). https://doi.org/10.1007/s10495-021-01664-2

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