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CTA095，一种新型的 Etk 和Src 双重抑制剂，可诱导前列腺癌细胞凋亡，并克服对Src 抑制剂的耐药性。

CTA095, a novel Etk and Src dual inhibitor, induces apoptosis in prostate cancer cells and overcomes resistance to Src inhibitors.

机构信息

Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, United States of America.

出版信息

PLoS One. 2013 Aug 15;8(8):e70910. doi: 10.1371/journal.pone.0070910. eCollection 2013.

DOI:10.1371/journal.pone.0070910
PMID:23967135
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3744530/
Abstract

Etk is a non-receptor tyrosine kinase, which provides a strong survival signal in human prostate cancer cells. Src, another tyrosine kinase that cross-activates with Etk, has been shown to play an important role in prostate cancer metastasis. Herein, we discovered a new class of Etk inhibitors. Within those inhibitors, CTA095 was identified as a potent Etk and Src dual inhibitor. CTA095 was found to induce autophagy as well as apoptosis in human prostate cancer cells. In addition, CTA095 inhibited HUVEC cell tube formation and "wound healing" of human prostate cancer cells, implying its role in inhibition of angiogenesis and metastasis of human prostate cancer. More interestingly, CTA095 could overcome Src inhibitor resistance in prostate cancer cells. It induces apoptosis in Src inhibitor resistant prostate cancer cells, likely through a mechanism of down regulation of Myc and BCL2. This finding indicates that simultaneously targeting Etk and Src could be a promising approach to overcome drug resistance in prostate cancer.

摘要

Etk 是一种非受体酪氨酸激酶，它为人类前列腺癌细胞提供了强烈的生存信号。Src 是另一种与 Etk 交叉激活的酪氨酸激酶，已被证明在前列腺癌转移中发挥重要作用。在此，我们发现了一类新的 Etk 抑制剂。在这些抑制剂中，CTA095 被鉴定为一种有效的 Etk 和 Src 双重抑制剂。CTA095 被发现可诱导人前列腺癌细胞自噬和凋亡。此外，CTA095 抑制 HUVEC 细胞管形成和人前列腺癌细胞的“伤口愈合”，表明其在抑制人前列腺癌血管生成和转移中的作用。更有趣的是，CTA095 可以克服前列腺癌细胞中的Src 抑制剂耐药性。它诱导 Src 抑制剂耐药的前列腺癌细胞凋亡，可能通过下调 Myc 和 BCL2 的机制。这一发现表明，同时靶向 Etk 和 Src 可能是克服前列腺癌药物耐药性的一种有前途的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/45cb96f01db6/pone.0070910.g013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/eb04829d13a2/pone.0070910.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/ea6ba64f94b8/pone.0070910.g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/45cb96f01db6/pone.0070910.g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/39f4b3e083d0/pone.0070910.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/07ef0640c8be/pone.0070910.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/2d4da3a605b8/pone.0070910.g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/79c691470595/pone.0070910.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/eb04829d13a2/pone.0070910.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/ea6ba64f94b8/pone.0070910.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/f7b18e45dda4/pone.0070910.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/fcdf9a1eec60/pone.0070910.g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d1/3744530/45cb96f01db6/pone.0070910.g013.jpg

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