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ELR510444 通过抑制 HIF 活性和破坏肾细胞癌中的微管来抑制肿瘤生长和血管生成。

ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.

机构信息

Department of Medicine and Institute for Drug Development, University of Texas Health Science Center, San Antonio, Texas, United States of America.

出版信息

PLoS One. 2012;7(1):e31120. doi: 10.1371/journal.pone.0031120. Epub 2012 Jan 25.

DOI:10.1371/journal.pone.0031120
PMID:22295124
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3266297/
Abstract

BACKGROUND

Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC.

PRINCIPAL FINDINGS

ELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis.

CONCLUSIONS

ELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascular disrupting and anti-angiogenic properties. Further investigation of ELR510444 for the therapy of RCC is warranted.

摘要

背景

缺氧诱导因子（HIF）是肾细胞癌（RCC）的一个有吸引力的治疗靶点，因为其由于von Hippel-Lindau（VHL）的缺失而导致的高表达促进了 RCC 的进展。考虑到这一点，我们假设 ELR510444，一种新型口服 HIF 活性小分子抑制剂，将减少血管生成并在 RCC 中具有显著活性。在 RCC 的体外和体内模型中研究了 ELR510444 的作用机制和治疗效果。

主要发现

ELR510444 降低了 HIF-1α 和 HIF-2α 的水平，降低了 RCC 细胞活力和集落形成存活，并诱导了细胞凋亡。VHL 缺陷型 RCC 细胞对 ELR510444 介导的细胞凋亡更敏感，而 VHL 的恢复促进了药物耐药性。更高浓度的 ELR510444 促进凋亡独立于 VHL 状态，可能是由于该药物对微管的不稳定作用。ELR510444 显著降低了 786-O 和 A498 RCC 异种移植模型中的肿瘤负担。这些作用与增加的坏死和凋亡以及血管生成的抑制有关。

结论

ELR510444 是一种很有前途的新型 HIF 抑制剂，可降低 RCC 细胞活力，诱导细胞凋亡，并减少 RCC 异种移植模型中的肿瘤负担。ELR510444 还使微管不稳定，表明其具有血管破坏和抗血管生成特性。进一步研究 ELR510444 治疗 RCC 是值得的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/a9f8942e9e96/pone.0031120.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/56954f7c9b8f/pone.0031120.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/cd03867c3c0d/pone.0031120.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/00ca03ce0cce/pone.0031120.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/ef28cf14652a/pone.0031120.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/b98256ff6656/pone.0031120.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/d0cab0ff3d3a/pone.0031120.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/a9f8942e9e96/pone.0031120.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/56954f7c9b8f/pone.0031120.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/cd03867c3c0d/pone.0031120.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/00ca03ce0cce/pone.0031120.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/ef28cf14652a/pone.0031120.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/b98256ff6656/pone.0031120.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/d0cab0ff3d3a/pone.0031120.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b65/3266297/a9f8942e9e96/pone.0031120.g007.jpg

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