力达霉素联合硼替佐米的抗骨髓瘤作用及对MAPKs表达的影响
Lidamycin Enhances Sensitivity of Multiple Myeloma to Bortezomid by Modulating Expression of Mitogen-activated Protein Kinases
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摘要: 目的 研究力达霉素(lidamycin, LDM)联合硼替佐米(bortezomib, BZM)的抗骨髓瘤作用及对丝裂原活化蛋白激酶(Mitogen-activated protein kinases, MAPKs)的影响，并探讨MAPKs在两药联合抗骨髓瘤中的作用。方法 选取适当的药物浓度和通路抑制剂浓度，MTS法检测细胞增殖情况；Western blot 检测相关蛋白及蛋白磷酸化水平。结果 BZM能增强LDM对骨髓瘤细胞的增殖抑制作用，LDM 激活c-Jun氨基末端激酶(c-Jun NH2-terminal kinase, JNK)、p38 MAPK的表达和细胞外信号调节激酶(Extracellular signal regulated rotein kinase, ERK)，两药联合后可使JNK和p38 MAPK的激活显著增强，而ERK的激活显著下降。JNK抑制剂(SP600125)、p38抑制剂(SB203580)和MEK抑制剂(U0126) 3种抑制剂单独作用对细胞的增殖抑制作用均不明显，但SP600125或SB203580分别与LDM联合BZM合用后均降低了两药联合对细胞的增殖抑制作用，而U0126与LDM联合BZM合用后提高了两药联合对细胞的增殖抑制作用。结论 LDM通过进一步激活JNK、p38 MAPK和降低ERK的激活来增强BZM抗骨髓瘤敏感度。Abstract: Objective To investigate the effect of lidamycin (LDM) combined with bortezomid (BZM) against multiple myeloma and the activative role of mitogen-activated protein kinases (MAPKs) in cell death after the combination treatment. Methods By selecting the appropriate concentrations of drugs and pathway inhibitors, cell proliferation was detected by MTS. The expression of JNK, p38 MAPK and ERK were detected by Western blot. Results LDM synergistically enhanced BZM-induced proliferation inhibition against human myeloma U266 cells. JNK, the expression of p38 MARK and ERK were activated by LDM. The activation of JNK and p38 MAPK were remarkably increased while ERK activation was decreased by the combined LDM and BZM. The inhibitors of JNK, p38 MAPK and MEK had no signifi cant effect on cell proliferation. JNK inhibitor (SP600125) or p38 MAPK inhibitor (SB203580) could reverse LDM plus BZM induced growth inhibition, conversely. MEK inhibitor (U0126) could synergistically enhance LDM plus BZM induced growth inhibition in U266 cells. Conclusion LDM greatly enhanced the sensitivity of multiple myeloma to BZM by further increasing the activation of JNK and p38 MAPK and decreasing the activation of ERK in U266 cells.
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