Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.
Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.
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DOI：
10.1371/journal.pone.0026943
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Park B;Prasad S;Yadav V;Sung B;Aggarwal BB
胰腺癌（PaCa）是最致命的癌症之一，即使给予患者最好的治疗，估计5年生存率<5%。此外，这些治疗通常是有毒和昂贵的，因此迫切需要安全、负担得起和有效的新药物。我们在这里描述了我们的研究结果与乙酰基-11-酮-β-乳香酸（AKBA），一种从阿育吠陀药物，乳香树脂的胶树脂。AKBA是否具有抗人PaCa的活性，在PaCa的体外模型和原位裸鼠模型中进行了检查。我们发现AKBA抑制了四种不同的PaCa细胞系（AsPC-1，PANC-28和具有K-Ras和p53突变的MIA PaCa-2，以及具有野生型K-Ras和p53突变的BxPC-3）的增殖。这些作用与抑制组成性活性NF-κB和抑制NF-κB调节基因表达有关。AKBA还诱导细胞凋亡，并使细胞对吉西他滨的凋亡作用敏感。在PaCa的原位裸鼠模型中，p.o.单独给予AKBA（100 mg/kg）显著抑制了肿瘤生长;吉西他滨增强了该活性。此外，AKBA抑制PaCa向脾、肝和肺的转移。这与肿瘤组织中增殖生物标志物Ki-67和微血管密度生物标志物CD 31的降低相关。AKBA显著降低了组织中NF-κB调控基因的表达。免疫组化结果显示AKBA可下调考克斯-2、MMP-9、CXCR 4和VEGF的表达。总之，这些结果表明，AKBA可以抑制原位裸鼠模型中人胰腺肿瘤的生长和转移，这与多个靶点的调节相关。
Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.