Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability

Xue, Qi; Hopkins, Benjamin D.; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E.

doi:10.1158/0008-5472.can-08-2058

Cited by 95 publications

(90 citation statements)

References 22 publications

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“…P529 has been previously shown to inhibit Akt signalling (Xue et al, 2008). Because inactivation of the Akt-mediated pathway is a demonstrated way to enhance the effect of RT (McKenna and Muschel, 2003;Cheng et al, 2006), we investigated whether P529 would increase radiation-induced PC-3 cell growth inhibition.…”

Section: P529 Enhances the Antiproliferative Effect Of Radiation In Pmentioning

confidence: 99%

“…Activation of Id-1-mediated pathways leads to the overexpression of the progangiogenic growth factor, VEGF . As P529 has been previously shown to inhibit angiogenesis in vivo (Xue et al, 2008), we analysed whether treatment of PC-3 cells with this drug would block VEGF/Id-1-angiogenic pathways. Administration of 2 mM P529 alone did not change Id-1 levels, whereas treatment with ionising radiation elevated Id-1 levels (Figure 4).…”

Section: P529 Inhibits Radiation-induced Overexpression Of Id-1 and Vegfmentioning

confidence: 99%

“…In this study, we have used the novel compound 8-(1-Hydroxyethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529, or P529) that has been recently shown to target Akt/mTOR pathways (Xue et al, 2008). This drug is a derivative of 3-hydroxy dibenzo [b,d]pyran-6-one, which was previously described to share structural similarities with the potent antiangiogenic and antitumour compound 2-methoxyestradiol, and to exhibit selective antiproliferative activity for endothelial cells (Schmidt et al, 2003).…”

mentioning

confidence: 99%

“…Recently, benzochromenones were reported to differentially suppress the growth of certain tumour cell lines (Dai et al, 2007). In addition, P529 showed to reduce tumour growth, angiogenesis, and vascular permeability in an in vivo model of glioblastoma (Xue et al, 2008).…”

mentioning

confidence: 99%

“…Our hypothesis was that as P529 inhibits the Akt pathway (Xue et al, 2008), which is critically involved in radioresistance (McKenna and Muschel, 2003;Cheng et al, 2006) and lacks in vivo toxicity (Xue et al, 2008), the use of this drug would be an excellent novel candidate to enhance the effect of RT in prostate cancer. Here, we show that, indeed, P529 potentiates the effect of RT in the aggressive prostate cancer cell line, PC-3, mainly through the blockade of p-Akt activation, but also through the alteration of other cancer-related pathways involving MMP-2, MMP-9, Id1, and vascular endothelial growth factor (VEGF).…”

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confidence: 99%

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The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

et al. 2009

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Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) o35 mM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg À1 P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.

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Section: P529 Enhances the Antiproliferative Effect Of Radiation In Pmentioning

confidence: 99%

Section: P529 Inhibits Radiation-induced Overexpression Of Id-1 and Vegfmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

et al. 2009

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The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways

et al. 2020

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Previous studies have proposed that the human papillomavirus (HPV) E6 oncoproteins modify the transcriptional activity of eIF4E through mechanisms dependent on p53 degradation. However, the effect of these oncoproteins on pathways regulating the activity of the eIF4E protein remains poorly understood. Hence, we investigated the mechanisms whereby E6 proteins regulate the activity of the eIF4E protein and its effect on target genes. Overexpression of E6 constructs (HPV-6, HPV-16, HPV-18, and HPV52) showed that E6 oncoproteins increased phosphorylation of the eIF4E protein (Serine-209). This result was mainly mediated by phosphorylation of the 4EBP1 protein via the PI3K/AKT pathway. Additionally, the pharmacological inhibition of eIF4E phosphorylation in cervical cancer cell lines substantially reduced the protein levels of CCND1 and ODC1, indicating that E6 of the high-risk genotypes may modify protein synthesis of the eIF4E target genes by increasing the activity of the AKT and ERK pathways.

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Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

et al. 2021

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Guanine‐rich sequences are known to fold into G‐quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H‐bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.

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Palomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular Permeability

Cited by 95 publications

References 22 publications

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways

Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

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