Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2011;6(10):e26943. doi: 10.1371/journal.pone.0026943. Epub 2011 Oct 31.
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.
胰腺癌（PaCa）是最致命的癌症之一，即使患者接受了最佳治疗，估计 5 年生存率仍<5%。此外，这些治疗方法往往具有毒性和昂贵，因此急需安全、负担得起且有效的新药物。我们在这里描述了我们对乙酰-11-酮-β-乳香酸（AKBA）的研究结果，AKBA 是一种从印度阿育吠陀药物乳香树胶中获得的药物。AKBA 是否对人胰腺癌细胞有活性，在体外模型和胰腺原位裸鼠模型中进行了检测。我们发现 AKBA 抑制了四种不同的胰腺癌细胞系（AsPC-1、PANC-28、具有 K-Ras 和 p53 突变的 MIA PaCa-2 和具有野生型 K-Ras 和 p53 突变的 BxPC-3）的增殖。这些作用与抑制组成性激活的 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。在胰腺原位裸鼠模型中，口服给予 AKBA（100mg/kg）单独给药可显著抑制肿瘤生长；这种活性可通过吉西他滨增强。此外，AKBA 抑制胰腺癌细胞向脾、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 CD31 的减少相关。AKBA 可使组织中 NF-κB 调节基因的表达显著降低。免疫组织化学分析还表明，AKBA 下调了组织中 COX-2、MMP-9、CXCR4 和 VEGF 的表达。总的来说，这些结果表明 AKBA 可以在与多种靶标调节相关的原位裸鼠模型中抑制人胰腺肿瘤的生长和转移。
