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Masanobu Tsubaki,Tomoya Takeda,Takuya Matsuda,Akihiro Kimura,Remi Tanaka,Sakiko Nagayoshi,Tadafumi Hoshida,Kazufumi Tanabe,Shozo Nishida 생화학분자생물학회 2023 BMB Reports Vol.56 No.2
Chronic myeloid leukemia (CML) has a markedly improvedprognosis with the use of breakpoint cluster region-abelson 1(BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However,approximately 40% of patients are resistant or intolerantto BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is ahypoxia response factor that has been reported to be highlyexpressed in CML patients, making it a therapeutic target forBCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors inducecell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death inBCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrationswhile the cell sensitivity was not affected with imatinibor dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition,echinomycin and PX-478 inhibited the c-Jun N-terminalkinase (JNK), Akt, and extracellular-regulated protein kinase 1/2(ERK1/2) activation via suppression of BCR-ABL1 and Met expressionin BCR-ABL1 sensitive and resistant CML cells. Moreover,treatment with HIF-1α siRNA induced cell death by inhibitingBCR-ABL1 and Met expression and activation of JNK,Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CMLcells. These results indicated that HIF-1α regulates BCR-ABL andMet expression and is involved in cell survival in CML cells,suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitorsare potential candidates for CML treatment.
Kaori Shoji,Kaori Shoji,Masanobu Tsubaki,Yuzuru Yamazoe,Takao Satou,Tatsuki Itoh,Yasuhiro Kidera,Yoshihiro Tanimori,Masashi Yanae,Hideaki Matsuda,Atsushi Taga,Haruyuki Nakamura,Shozo Nishida 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.3
Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (C-glucosylxanthone), is a xanthone derivative that is widely distributed in higher plants. Recently, mangiferin was found to exhibit potential antitumor effects. However, the molecular mechanisms of this effect have not been elucidated. In the present study, we attempt to clarify the mechanism of mangiferininduced apoptosis in the human acute myeloid leukemia cell line HL-60; mangiferin was found to induce apoptosis. We also observed a concurrent increase in caspase-3 activity and DNA fragmentation. Furthermore, on examining the survival signals expressed during apoptotic induction, we observed that mangiferin caused a remarkable decrease in the nuclear entry of NF-κB p65. However, there were no changes in the expression of other survival signals,such as extracellular signal-regulated kinase 1/2, protein kinase B, and p38 mitogenactivated protein kinase. In addition, mangiferin suppressed the expressions of Bcl-xL and XIAP; however, we did not note any changes in the levels of Bcl-2, Bax, and Bim. These results indicate that mangiferin induces apoptosis by suppressing NF-κB activation and expressions of Bcl-xL and XAIP. These findings suggest that mangiferin may be useful as an anticancer agent and can be used in combination therapy with other anticancer drugs for the treatment of acute myeloid leukemia.