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

李 禹霖 富山大学

2022.09.28

概要

〔⽬的〕
Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. AML progresses rapidly and is typically fatal within weeks or months if left untreated. BTO- 956 is a known anticancer drug. Therefore, I synthesized novel compound based on the structure of BTO-956 and named TA. In the present study, I tried to determine the anti- cancer effects of TA and to reveal its underlying molecular mechanism in human myelomonocytic lymphoma cells.

〔⽅法並びに成績〕
Human myelomonocytic lymphoma (U937) and promyeloblast (HL-60) cells were treated with TA, then incubated for 6 h at 37 ℃ with 5% CO2 and 95% air. All inhibitors at the indicated concentrations were added to the samples 1 h before TA treatment, as a pretreatment. Cell viability was measured by Cell Counting Kit-8 or MTT assay. Apoptosis was examined by Hoechst-stained fluorescene microscopy, DNA fragmentation and SubG1 assay using flow cytometry. Mitochondrial membrane potential (MMP) and generation of intracellular reactive oxygen species (ROS) were detected by TMRM and DHE, respectively, using flow cytometry. The protein expression levels of apoptosis, antioxidant enzymes, endoplasmic reticulum (ER) stress, autophagy and mitogen-activated protein kinase (MAPK) signaling pathways were analyzed by western blot.
TA decreased cell viability in a dose- and time-dependent manner in U937 and HL 60 cells. DNA fragmentation and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP) were significantly increased by TA treatment for 6 h in U937 cells. TA increased SubG1 population and the number of apoptotic bodies. Further, TA significantly induced apoptosis in U937 cells through production of intracellular ROS, dysfunction of mitochondria. TA significantly decreased Sirt1, Gpx-1 and SOD-2 expression levels. TA markedly increased pro-apoptotic proteins Bax and t-Bid. In contrast, anti-apoptotic proteins, including Mcl-1 and Bcl-2, expression levels were significantly decreased after treatment with TA. MAPK signaling pathways were also involved, up-regulating phosphorylation levels of ERK, JNK, and P38. 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 attenuated and aggravated TA-induced apoptosis, respectively. TUDCA dramatically decreased TA- induced SubG1 population, expression levels of cleavage of caspase-3 and PARP. Conversely, 3-MA aggravated TA-induced XIAP reduction, and cleaved-caspase-3, cleaved-PARP increase. Cell viability of solid tumor cell lines, HeLa, HepG2, MCF-7 and AGS cells, were also significantly decreased by treatment of TA in a dose- and time- dependent manner.

〔総括〕
In conclusion, TA markedly increased apoptosis in U937 cells with the involvement of the MAPK pathway via exaltation of intracellular ROS, activation of ER stress, and initiation of the apoptotic pathway. Activation of apoptosis is accompanied by an anti- apoptotic autophagy. My results indicated that TA combined with autophagy inhibitor can induce cancer cell death via a unique but complicated pathway, which may refer to the exploration of a novel therapeutic approach not only for leukemia but also other solid cancer cells.

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