Pseudolaric Acid B Inhibits Angiogenesis and Reduces Hypoxia-Inducible Factor 1α by Promoting Proteasome-Mediated Degradation

Li, Meihong; Miao, Ze‐Hong; Tan, Wenfu; Yue, Jian‐Min; Zhang, Chao; Lin, Liping; Zhang, Xiongwen; Ding, Jian

doi:10.1158/1078-0432.ccr-04-0951

Cited by 80 publications

(68 citation statements)

References 33 publications

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“…Although the involvement of mitogenactivated protein kinase (MAPK) pathway in maintaining the stability of HIF-1a has been contradictory in literature (Richard et al, 1999;Hur et al, 2001), we and others have shown that inhibition of p42/p44 ERKs by PD98059 diminished the stability of HIF-1a (Yoo et al, 2003(Yoo et al, , 2004Li et al, 2004;Zhang et al, 2005). Consistent with the previous results, activation of p42/p44 ERKs as well as stability of HIF-1a was significantly induced under hypoxia and repressed by PD98059 ( Figure 3d) (Yoo et al, 2003(Yoo et al, , 2004Li et al, 2004;Zhang et al, 2005). Similarly, 6-MP increased phosphorylated p42/p44 ERKs, whereas PD98059 decreased the phosphorylation of p42/p44 as well as the protein level of both HIF-1a and Nur77 ( Figure 3d).…”

Section: -Mp Enhances Transcriptional Activity Of Hif-1a Y-g Yoo Et Almentioning

confidence: 98%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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Hypoxia-inducible factor-1a (HIF-1a) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1a. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1a as well as vascular endothelial growth factor (VEGF) in a dose-and timedependent manner. The induction of HIF-1a was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1a protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1a protein. The fact that 6-MP decreased the association of HIF-1a with von Hippel-Lindau protein and the acetylation of HIF-1a, may explain how 6-MP induced stability of HIF-1a. Further, 6-MP induced the transactivation function of HIF-1a by recruiting co-activator cyclic-AMP-responseelement-binding protein. Finally, 6-MP enhanced the expression of HIF-1a and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1a and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

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Section: -Mp Enhances Transcriptional Activity Of Hif-1a Y-g Yoo Et Almentioning

confidence: 98%

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

et al. 2006

Oncogene

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“…We also found that of the 17 identified antiangiogenic compounds, 4 compounds, namely, pseudolaric acid B, MFTZ-1, 10-hydroxycamptothecin and triptolide, can indirectly inhibit the VEGF-VEGFR axis by decreasing cellular HIF-1α accumulation and thereby reducing VEGF expression and secretion [15][16][17][18][19][20][21] (Figure 1). We define these compounds to be HIF-1α-VEGF axis inhibitors.…”

Section: Hif-1α-vegf Axis Inhibitorsmentioning

confidence: 85%

“…Pseudolaric acid B targets microtubulin and causes its depolymerization [22,23] . Pseudolaric acid B inhibits angiogenesis by reducing the stability of HIF-1α and thereby downregulating the VEGF-VEGFR axis [15,16,18] . However, there has been no direct evidence indicating any association between its antiangiogenic activity and its inhibition of microtubulin [23,24] .…”

Section: Hif-1α-vegf Axis Inhibitorsmentioning

confidence: 99%

Newly discovered angiogenesis inhibitors and their mechanisms of action

Feng

Ding

2012

Acta Pharmacol Sin

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In the past decade, the success of angiogenesis inhibitors in clinical contexts has established the antiangiogenic strategy as an important part of cancer therapy. During that time period, we have discovered and reported 17 compounds that exert potent inhibition on angiogenesis. These compounds exhibit tremendous diversity in their sources, structures, targets and mechanisms. These studies have generated new models for further modification and optimization of inhibitory compounds, new information for mechanistic studies and a new drug candidate for clinical development. In particular, through studies on the antiangiogenic mechanism of pseudolaric acid B, we discovered a novel mechanism by which the stability of hypoxia-inducible factor 1α is regulated by the transcription factor c-Jun. We also completed a preclinical study of AL3810, a compound with the potential to circumvent tumor drug resistance to a certain extent. All of these findings will be briefly reviewed in this article.

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“…PAB also showed strong cytotoxic activity. In our collaboration study, this compound was found for the first time to have strong antiangiogenic activity with a unique mode of antitumor action [118][119][120] . A structural modification of PAB was thus conducted, and more than 40 derivatives were prepared in the first round.…”

Section: Miscellaneousmentioning

confidence: 92%

Discovery of structurally diverse and bioactive compounds from plant resources in China

Shi

Yue

2012

Acta Pharmacol Sin

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This review describes the major discoveries of structurally diverse and/or biologically significant compounds from plant resources in China, mainly from the traditional Chinese medicines (TCMs) since the establishment of our research group in 1999. In the past decade, a large array of biologically significant and novel structures has been identified from plant resources (or TCM) in our laboratory. The structural modification of several biologically important compounds led to more than 400 derivatives, some of which exhibited significantly improved activities and provided opportunities to elucidate the structure-activity relationship of the related compound class. These findings are important for drug discovery and help us understand the biological basis for the traditional applications of these plants in TCM.

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Pseudolaric Acid B Inhibits Angiogenesis and Reduces Hypoxia-Inducible Factor 1α by Promoting Proteasome-Mediated Degradation

Cited by 80 publications

References 33 publications

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

Newly discovered angiogenesis inhibitors and their mechanisms of action

Discovery of structurally diverse and bioactive compounds from plant resources in China

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