Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis
Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis
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DOI：
10.1182/blood-2005-01-0346
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发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Ishitsuka, K;Hideshima, T;Anderson, KC
和厚朴（Honokaline，HNK）是从传统中药和日本医药中使用的植物蒲公英中提取的有效成分。在这里，我们表明，HNK显着诱导细胞毒性的人多发性骨髓瘤（MM）细胞系和肿瘤细胞的复发性难治性MM患者。无论是与骨髓基质细胞，也不是细胞因子（白细胞介素-6和胰岛素样生长因子-1）共培养保护HNK诱导的细胞毒性。虽然半胱天冬酶3、7、8和9的活化由HNK触发，但泛半胱天冬酶抑制剂z-VAD-favorite并不消除HNK诱导的细胞凋亡。重要的是，半胱天冬酶非依赖性细胞凋亡的执行者，细胞凋亡诱导因子（AIF）从线粒体的释放是由HNK处理诱导的。HNK诱导SU-DHL 4细胞系中的细胞凋亡，该细胞系具有与对常规和新型药物的抗性相关的低水平的半胱天冬酶3和8。这些结果表明，HNK诱导细胞凋亡通过caspase依赖性和非依赖性途径。此外，HNK增强硼替佐米诱导的MM细胞毒性和凋亡。除了对MM细胞的直接细胞毒性外，HNK还抑制内皮细胞的管形成，表明HNK抑制骨髓微环境中的新血管形成。综上所述，我们的研究结果为HNK改善MM患者结局的临床方案提供了临床前依据。
Honokiol (HNK) is an active component purified from magnolia, a plant used in traditional Chinese and Japanese medicine. Here we show that HNK significantly induces cytotoxicity in human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM. Neither coculture with bone marrow stromal cells nor cytokines (interleukin-6 and insulin-like growth factor-1) protect against HNK-induced cytotoxicity. Although activation of caspases 3, 7, 8, and 9 is triggered by HNK, the pan-caspase inhibitor z-VAD-fmk does not abrogate HNK-induced apoptosis. Importantly, release of an executioner of caspase-independent apoptosis, apoptosis-inducing factor (AIF), from mitochondria is induced by HNK treatment. HNK induces apoptosis in the SU-DHL4 cell line, which has low levels of caspase 3 and 8 associated with resistance to both conventional and novel drugs. These results suggest that HNK induces apoptosis via both caspase-dependent and -independent pathways. Furthermore, HNK enhances MM cell cytotoxicity and apoptosis induced by bortezomib. In addition to its direct cytotoxicity to MM cells, HNK also represses tube formation by endothelial cells, suggesting that HNK inhibits neovascurization in the bone marrow microenvironment. Taken together, our results provide the preclinical rationale for clinical protocols of HNK to improve patient outcome in MM.