A novel combinatorial nanotechnology-based oral chemopreventive regimen demonstrates significant suppression of pancreatic cancer neoplastic lesions.
A novel combinatorial nanotechnology-based oral chemopreventive regimen demonstrates significant suppression of pancreatic cancer neoplastic lesions.
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DOI：
10.1158/1940-6207.capr-13-0172
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Prabhu S
中科院分区：
文献类型：
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作者：
Grandhi BK;Thakkar A;Wang J;Prabhu S
胰腺癌是一种致命的疾病，每年导致37,000名美国人死亡。尽管对治疗方案进行了20年的研究，但确诊后的生存率仍<5%。最近，化学预防策略作为一种替代治疗方法获得了相当大的关注。我们之前已经证明阿司匹林（ASP）、姜黄素（CUR）和萝卜硫素（SFN） （ACS）低剂量联合使用对胰腺癌细胞系有显著的体外化学预防作用。在这里，我们报告了一项为期24周的化学预防研究的结果，该研究使用(1)未修饰的（游离药物）ACS组合和(2)纳米封装的（固体脂质纳米颗粒；SLN） ASP， CUR和游离SFN组合，在n -亚硝基双（2-氧丙基）胺（BOP）处理的叙利亚金仓鼠模型上口服ACS组合来抑制胰腺上皮内肿瘤（PanINs）的进展。使用三种不同剂量（低、中、高）的未修饰ACS组合，肿瘤发病率分别降低18%、50%和68.7%；而改良的纳米封装ACS方案与自由药物组合相比，在低10倍的剂量下，肿瘤发生率分别降低了33%，67%和75%。同样，未修饰的自由ACS显示出细胞增殖的显著降低，而SLN包封的ACS方案显示细胞增殖的显著降低，分别为6.3%，58.6%和72.8%，由PCNA表达证实。与BOP对照组相比，细胞凋亡指标分别上调1.5倍、2.8倍和3.2倍。这些研究为使用口服、低剂量、基于纳米技术的组合方案进行胰腺癌的长期化学预防提供了概念验证。
Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still <5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low dose combinations of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanINs) using (1) unmodified (free drug) combinations of ACS, and (2) nanoencapsulated (solid-lipid nanoparticles; SLN) combinations of ASP, CUR and free SFN. The use of three different doses (low, medium and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50% and 68.7% respectively; whereas the modified nano-encapsulated ACS regimens reduced tumor incidence by 33%, 67% and 75%, respectively, at 10X lower dose compared to the free drug combinations. Similarly, while the unmodified free ACS demonstrated a notable reduction in cell proliferation, the SLN encapsulated ACS regimens, showed significant reduction in cell proliferation at 6.3%, 58.6 % and 72.8 % as evidenced by PCNA expression. Cell apoptotic indices were also up regulated by 1.5X, 2.8X and 3.2X respectively, compared to BOP control. These studies provide a proof-of-concept for the use of an oral, low dose, nanotechnology-based combinatorial regimen for the long term chemoprevention of pancreatic cancer.