Zhang Nan, Wang Dong, Zhu Yu, Wang Jian, Lin Hong
Department of Pharmacology, Tianjin Children's Hospital, Tianjin, China E-mail :
Asian Pac J Cancer Prev. 2014;15(22):9915-9. doi: 10.7314/apjcp.2014.15.22.9915.
Lamellarin D (LamD) is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cells, affecting cell growth and inducing apoptosis. However, the molecular mechanisms of action of this compound are poorly understood. In this study, the anticancer efficacy of LamD was investigated in human leukemia K562 cells. The results showed suppressed cell proliferation and induction of G0/G1-phase arrest,while expression of CDK1, and activity of smad3 and smad5 were reduced, but that of p27, p53 and STGC3 was increased. LamD induced cell apoptosis through activation of caspases-8/-3, inhibition of survivin and Bcl-2, suggesting that this compound may also act through a caspase-independent pathway. Moreover, LamD inhibited the secretion of TGF-β, IL-1β, IL-6, IL-8 and other inflammatory cytokines and the transcriptional activity of transcription factor NF-κB in human leukemia K562 cells. Taken together, our results suggest that LamD-mediated inhibition of leukemia cell proliferation may be related to the induction of apoptosis and the regulation of cell cycle, tumor- related gene expression and cytokine expression, which may provide a new way of thinking for the treatment leukemia.
海兔毒素D（LamD）是一种海洋生物碱，对多种癌细胞具有显著的细胞毒性，可影响细胞生长并诱导细胞凋亡。然而，这种化合物的分子作用机制尚不清楚。在本研究中，我们研究了LamD对人白血病K562细胞的抗癌效果。结果显示细胞增殖受到抑制，细胞被阻滞在G0/G1期，同时细胞周期蛋白依赖性激酶1（CDK1）的表达以及Smad3和Smad5的活性降低，而p27、p53和STGC3的表达增加。LamD通过激活半胱天冬酶-8/-3、抑制生存素和Bcl-2诱导细胞凋亡，这表明该化合物也可能通过半胱天冬酶非依赖性途径发挥作用。此外，LamD抑制人白血病K562细胞中转化生长因子-β（TGF-β）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和其他炎性细胞因子的分泌以及转录因子核因子-κB（NF-κB）的转录活性。综上所述，我们的结果表明，LamD介导的白血病细胞增殖抑制可能与诱导细胞凋亡以及调节细胞周期、肿瘤相关基因表达和细胞因子表达有关，这可能为白血病的治疗提供新的思路。
