Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells.
Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells.
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DOI：
10.1371/journal.pone.0021573
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Singh AP
中科院分区：
文献类型：
--
作者：
Arora S;Bhardwaj A;Srivastava SK;Singh S;McClellan S;Wang B;Singh AP
胰腺癌患者的生存率极低，因为其无症状进展至晚期和转移性阶段，目前的治疗在很大程度上仍然无效。因此，需要新的治疗剂和治疗方法来改善临床结果。在这项研究中，我们确定了和厚朴酚，一种生物活性成分的东方草药厚朴/grandiflora，对两个胰腺癌细胞系，MiaPaCa和Panc1，单独和与标准的化疗药物，吉西他滨组合的影响。和厚朴酚对胰腺癌细胞株均具有生长抑制作用，其作用机制是使细胞周期阻滞于G1期，诱导细胞凋亡。在分子水平上，和厚朴显著降低细胞周期蛋白（D1和E）和细胞周期蛋白依赖性激酶（Cdk 2和Cdk 4）的表达，并引起Cdk抑制剂p21和p27的增加。此外，和厚朴治疗导致Bax/Bcl-2和Bax/Bcl-xL比率增加，有利于胰腺癌细胞的凋亡。这些变化伴随着NF-κ B在细胞质中的积累增加，同时伴随着核分数的减少和NF-κ B应答启动子的转录活性降低。这与κ B α抑制剂（I κ B-α）磷酸化降低相关，导致其稳定，从而增加细胞水平。重要的是，和诺啡肽还通过限制吉西他滨诱导的NF-κ B在治疗的胰腺癌细胞系中的核积累，部分增强吉西他滨的细胞毒性作用。总而言之，这些发现首次证明了honokaline在胰腺癌中的生长抑制作用，并表明其作为一种新型天然药物在预防和治疗中的潜在用途。
Survival rates for patients with pancreatic cancer are extremely poor due to its asymptomatic progression to advanced and metastatic stage for which current therapies remain largely ineffective. Therefore, novel therapeutic agents and treatment approaches are desired to improve the clinical outcome. In this study, we determined the effects of honokiol, a biologically active constituent of oriental medicinal herb Magnolia officinalis/grandiflora, on two pancreatic cancer cell lines, MiaPaCa and Panc1, alone and in combination with the standard chemotherapeutic drug, gemcitabine. Honokiol exerted growth inhibitory effects on both the pancreatic cancer cell lines by causing cell cycle arrest at G1 phase and induction of apoptosis. At the molecular level, honokiol markedly decreased the expression of cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4), and caused an increase in Cdk inhibitors, p21 and p27. Furthermore, honokiol treatment led to augmentation of Bax/Bcl-2 and Bax/Bcl-xL ratios to favor apoptosis in pancreatic cancer cells. These changes were accompanied by enhanced cytoplasmic accumulation of NF-κB with a concomitant decrease in nuclear fraction and reduced transcriptional activity of NF-κB responsive promoter. This was associated with decreased phosphorylation of inhibitor of kappa B alpha (IκB-α) causing its stabilization and thus increased cellular levels. Importantly, honokiol also potentiated the cytotoxic effects of gemcitabine, in part, by restricting the gemcitabine-induced nuclear accumulation of NF-κB in the treated pancreatic cancer cell lines. Altogether, these findings demonstrate, for the first time, the growth inhibitory effects of honokiol in pancreatic cancer and indicate its potential usefulness as a novel natural agent in prevention and therapy.
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影响因子：
254.7
作者：
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通讯作者：
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