N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells
N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells
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DOI：
10.1080/10428190500080595
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发表时间：
2005-06-01
影响因子：
2.6
通讯作者：
Gerson, SL
中科院分区：
文献类型：
--
作者：
Bahlis, NJ;Miao, YL;Gerson, SL
多发性骨髓瘤是浆细胞的克隆性恶性肿瘤，其总是进展到化学抗性状态。PI 3 K/Akt通路介导参与骨髓瘤发病机制的几种生长因子的下游信号，并且在骨髓瘤细胞中观察到Akt的组成性激活。我们现在报道了星形孢菌素衍生物，N-苯甲酰化星形孢菌素或PKC 412，诱导骨髓瘤细胞系（RPMI 8226 S，U266，MM 1 S和MM 1 R）的细胞死亡，线粒体膜电位Δ psi（m），半胱天冬酶3和PARP裂解的损失。ZVAD。而不是白细胞介素-6，从PKC 412的作用中拯救了这些细胞。在线粒体上游，PKC 412通过抑制其激活环中丝氨酸残基的磷酸化来抑制Bad磷酸化并减弱Akt激酶活性。还注意到下游Akt底物GSK 3 α/β和FKHR的磷酸化减少。用组成型活性Akt（8226 S-myAkt）稳定转染8226 S细胞可部分保护其免受PKC 412细胞毒性。从难治性骨髓瘤患者（n = 4）分离的原代骨髓瘤细胞对PKC 412治疗同样敏感。更重要的是，PKC 412不影响CFU-GM或BFU-E集落形成。总之，我们的研究结果表明，PKC 412抑制Akt激酶的激活，并诱导骨髓瘤细胞系，以及原代耐药细胞的凋亡。PKC 412是多发性骨髓瘤新治疗方案的合适候选者。
Multiple myeloma is a clonal malignancy of plasma cells that invariably progresses to a chemoresistant state. The PI3K/Akt pathway mediates signals downstream of several growth factors involved in myeloma pathogenesis, and constitutive activation of Akt was observed in myeloma cells. We now report that a staurosporine derivative, N-benzoylated staurosporine or PKC412, induces cell death in myeloma cell lines ( RPMI8226S, U266, MM1S and MM1R) with loss of mitochondrial membrane potential Delta psi(m), caspase 3 and PARP cleavage. ZVAD. fmk, but not interleukin-6, rescued these cells from PKC412 effects. Upstream of the mitochondria, PKC412 inhibited Bad phosphorylation and attenuated Akt kinase activity by suppressing its phosphorylation on serine residue in its activation loop. Reduced phosphorylation of downstream Akt substrates GSK3 alpha/beta and FKHR was also noted. Stable transfection of 8226S cells with constitutively active Akt ( 8226S-myAkt) partially protected against PKC412 cytotoxicity. Primary myeloma cells isolated from refractory myeloma patients (n = 4), were equally sensitive to PKC412 treatment. More importantly, PKC412 did not affect CFU-GM or BFU-E colony formation. In summary, our results demonstrate that PKC412 suppresses Akt kinase activation and induces apoptosis in myeloma cell lines, as well as primary resistant cells. PKC412 is an appropriate candidate for novel treatment protocols for multiple myeloma.