PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft
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Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.
KeywordsMultiple myeloma Stromal cells Homoharringtonine (HHT) LY294002 PI3K/Akt signaling pathways
This research is granted by the Fujian Provincial Innovation Fund (2014-CX-13), Fujian Provincial Natural Fund (2015J01472), Fujian Medical University Professor Fund (JS14024), Personnel Training Program of Fujian Provincial Health System for Youth Backbone Talents (2014-ZQN-JC-10), Construction Project of Fujian Medical Center of Hematology (Min201704), and National and Fujian Provincial Key Clinical Specialty Discipline Construction Program, P. R. C.
Compliance with ethical standards
Primary MM cells were isolated from the patients in the Fujian Medical University Union Hospital with informed consent and institutional review board approval. The use of animals was approved by the Committee of Research Animals of Fujian Medical University.
Conflict of interest
The authors declare that they have no conflict of interest.
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