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BI-69A11通过靶向Akt增强结肠癌细胞对mda-7/IL-24诱导的生长抑制的敏感性。

BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt.

作者信息

Pal I, Sarkar S, Rajput S, Dey K K, Chakraborty S, Dash R, Das S K, Sarkar D, Barile E, De S K, Pellecchia M, Fisher P B, Mandal M

机构信息

School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.

Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.

出版信息

Br J Cancer. 2014 Jul 8;111(1):101-11. doi: 10.1038/bjc.2014.227. Epub 2014 Jun 3.

DOI:10.1038/bjc.2014.227
PMID:24892445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4090725/
Abstract

BACKGROUND

Akt and its downstream signalling pathways contribute to the aetiology and progression of colorectal carcinoma (CRC). Targeting the Akt pathway is an attractive strategy but few chemotherapeutic drugs have been used to treat CRC with only limited success. BI-69A11, a small molecule inhibitor of Akt, efficiently inhibits growth in melanoma cells. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 promotes cancer-selective apoptosis when delivered by a tropism-modified replication incompetent adenovirus (Ad.5/3-mda-7). However, Ad.5/3-mda-7 displays diminished antitumour efficacy in several CRC cell lines, which correlates with the expression of K-RAS.

METHODS

The individual and combinatorial effect of BI-69A11 and Ad.5/3-mda-7 in vitro was studied by cell viability, cell cycle, apoptosis and invasion assays in HT29 and HCT116 cells containing wild type or mutant K-ras, respectively. In vivo HT29 tumour xenografts were used to test the efficacy of the combination treatment.

RESULTS

BI-69A11 inhibited growth and induced apoptosis in CRC. However, combinatorial treatment was more effective compared with single treatment. This combination showed profound antitumour and anti angiogenic effects in vitro and in vivo by downregulating Akt activity.

CONCLUSIONS

BI-69A11 enhances the antitumour efficacy of Ad.5/3-mda-7 on CRC overexpressing K-RAS by inducing apoptosis and regulating Akt activity thereby warranting further evaluation in treating CRC.

摘要

背景

Akt及其下游信号通路在结直肠癌（CRC）的病因学和进展中起作用。靶向Akt通路是一种有吸引力的策略，但很少有化疗药物用于治疗CRC，且效果有限。BI-69A11是一种Akt小分子抑制剂，可有效抑制黑色素瘤细胞的生长。黑色素瘤分化相关基因-7（mda-7）/白细胞介素-24通过嗜性修饰的无复制能力腺病毒（Ad.5/3-mda-7）递送时可促进癌症选择性凋亡。然而，Ad.5/3-mda-7在几种CRC细胞系中的抗肿瘤功效降低，这与K-RAS的表达相关。

方法

通过细胞活力、细胞周期、凋亡和侵袭试验，分别研究了BI-69A11和Ad.5/3-mda-7在含有野生型或突变型K-ras的HT29和HCT116细胞中的单独及联合作用。在体内，使用HT29肿瘤异种移植物来测试联合治疗的疗效。

结果

BI-69A11抑制CRC的生长并诱导其凋亡。然而，联合治疗比单一治疗更有效。这种联合通过下调Akt活性在体外和体内均显示出显著的抗肿瘤和抗血管生成作用。

结论

BI-69A11通过诱导凋亡和调节Akt活性增强了Ad.5/3-mda-7对过表达K-RAS的CRC的抗肿瘤功效，因此值得在CRC治疗中进一步评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/54de2c144c82/bjc2014227f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/27a5ef6ccf54/bjc2014227f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/bcb47782ff65/bjc2014227f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/84fe8f3b5746/bjc2014227f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/9263aba01f0e/bjc2014227f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/39246323fd30/bjc2014227f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/279299f21aa6/bjc2014227f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/01b29a197005/bjc2014227f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/54de2c144c82/bjc2014227f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/27a5ef6ccf54/bjc2014227f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/bcb47782ff65/bjc2014227f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/84fe8f3b5746/bjc2014227f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/9263aba01f0e/bjc2014227f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/39246323fd30/bjc2014227f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/279299f21aa6/bjc2014227f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/01b29a197005/bjc2014227f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9229/4090725/54de2c144c82/bjc2014227f8.jpg

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