Stellettin B induces apoptosis in human chronic myeloid leukemia cells via targeting PI3K and Stat5.

Yali Chen,Dexin Kong,Yuxu Zhong,Yuling Qiu,Guanwei Fan,Ran Wang,Zhe Zhang,Meihua Jin,Lei Zhang,Qianxiang Zhou

doi:10.18632/oncotarget.15957

Yali Chen, Dexin Kong + Show 8 more

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https://doi.org/10.18632/oncotarget.15957

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Abstract

Novel agents are still urgently expected for therapy of chronic myeloid leukemia (CML). The in vitro anti-leukemia activity of Stellettin B (Stel B), a triterpenoid we isolated from marine sponge Jaspis stellifera, on human CML K562 and KU812 cells was recently investigated. Stel B inhibited K562 and KU812 cell proliferation with IC50 as 0.035 μM and 0.95 μM respectively. While no obvious cell cycle arrest was observed, apoptosis was induced in K562 cells after Stel B treatment. The Stel B-induced apoptosis might be in mitochondrial pathway, with increase of Bad and Bax, decrease of Bcl-2 and activation of caspase-9. In addition, dose-dependent increase of reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) occurred. Meanwhile, Stel B inhibited phosphorylation of Stat5, expression of 4 PI3K catalytic isoforms, and phosphorylation of the downstream effectors including PDK1 and Akt, suggesting that inhibition against Stat5 and PI3K might be involved in the apoptosis-inducing effect. Combination of Stel B with Imatinib with ratio as IC50 Stel B: 5×IC50 Imatinib led to synergistic effect. Stel B might become a promising candidate for CML therapy alone or together with Imatinib.

Highlights

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by Philadelphia (Ph) chromosome
K562 cells were exposed to various concentrations (0, 0.002, 0.006, 0.018, 0.054, 0.162, 0.486, 1.458 μM) of Stellettin B (Stel B) for 48 h, cell viability was determined by WST-8 assay
We demonstrated that Stel B inhibited the proliferation of K562 chronic myeloid leukemia (CML) cells potently with an IC50 of low nM

Summary

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by Philadelphia (Ph) chromosome. The oncoprotein Bcr-Abl, generated from Ph chromosome, is constitutively activated in CML and leads to uncontrolled cell proliferation [1, 2]. Bcr-Abl inhibitors like Imatinib, Nilotinib and Dasatinib, highly improved the clinical therapy of CML in the past years. Drug resistance, early relapse and persistence of leukemic stem cells led to the limited outcome of Bcr-Abl inhibitor monotherapy [3]. Natural products often serve as drug leads for cancer therapy because of their mechanistic diversity and good availability [4, 5]. Marine sponges are known to be productive source of anticancer drug leads [5,6,7]. Stellettin B (Stel B) is an isomalabaricane triterpenoid that we isolated from marine sponge Jaspis stellifera [10]. Stel B showed antiproliferative, cell cycle G1-arrest, apoptosis-inducing, as well as autophagy-inducing activities on human solid tumor cells including non-small cell lung cancer (NSCLC) A549 [11]

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