WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth

Wang, Liangyou; Sloper, Daniel T.; Addo, Sadiya N.; Tian, Defeng; Slaton, Joel W.; Xing, Chengguo

doi:10.1158/0008-5472.can-07-6590

Cited by 34 publications

(11 citation statements)

References 27 publications

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“…Therefore, the VEGF–Bcl-2–CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies. And nowadays, short interfering RNA and small molecule inhibitors of Bcl-2 are being developed to inhibit solid tumors (46–48). In our present investigation, we demonstrated that treatment of (−)-gossypol led to obvious downregulation of VEGF in both cancer cells and endothelial cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

Pang

Wu²,

Lu³

et al. 2011

Molecular Cancer Therapeutics

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(−)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (−)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we demonstrated that (−)-gossypol dose-dependently inhibited the expression of vascular endothelial growth factor (VEGF), Bcl-2 and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and human primary cultured umbilical vein endothelial cells (HUVECs) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at dosage of 15 mg/kg/d. This inhibitory action of (−)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (−)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells, and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (−)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, VEGF-triggered phosphorylation of key intracellular proangiogenic molecules, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase and AKT kinase, were all suppressed by the treatment. Taken together, the present study demonstrates that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.

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Section: Discussionmentioning

confidence: 99%

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

Pang

Wu²,

Lu³

et al. 2011

Molecular Cancer Therapeutics

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“…The compound has gone through several clinical II studies for the treatment of patients with solid tumors and hematopoietic malignancies ( Shoemaker et al, 2006 ). On the other hand, optimization of BH3I-1 led to the discovery of WL-276 ( 11 in Figure 7 ) ( Wang et al, 2008 ) with a similar inhibitory activity against Bcl-2 and enhanced inhibitory activity against Bcl-X L as compared with gossypol. In contrast, WL-276 effectively induces apoptosis in PC-3 cells at low micromolar concentrations.…”

Section: The Bh3-bcl-2 Interactionmentioning

confidence: 99%

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Pérez

2021

Front. Mol. Biosci.

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Protein-protein interactions (PPIs) mediate a large number of important regulatory pathways. Their modulation represents an important strategy for discovering novel therapeutic agents. However, the features of PPI binding surfaces make the use of structure-based drug discovery methods very challenging. Among the diverse approaches used in the literature to tackle the problem, linear peptides have demonstrated to be a suitable methodology to discover PPI disruptors. Unfortunately, the poor pharmacokinetic properties of linear peptides prevent their direct use as drugs. However, they can be used as models to design enzyme resistant analogs including, cyclic peptides, peptide surrogates or peptidomimetics. Small molecules have a narrower set of targets they can bind to, but the screening technology based on virtual docking is robust and well tested, adding to the computational tools used to disrupt PPI. We review computational approaches used to understand and modulate PPI and highlight applications in a few case studies involved in physiological processes such as cell growth, apoptosis and intercellular communication.

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“…Isolation of the fragmented DNA is then done using such common methods for genomic DNA isolation as phenol-chloroform [15,41,43,44], or phenol-chloroform-isoamyl alcohol extraction [45]. A number of isolation procedures based on various physical and chemical principles are used for isolating apoptotic low molecular weight DNA fragments from apoptotic cells [46][47][48][49][50][51][52]. Commercial kits for this purpose mostly use solid-phase extraction on, for example, silica gel or glass fiber fleece.…”

Section: Dna Ladder Assaymentioning

confidence: 99%

An overview of apoptosis assays detecting DNA fragmentation

2018

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Apoptosis has been recognized as a type of programmed cell death connected with characteristic morphological and biochemical changes in cells. This programmed cell death plays an important role in the genesis of a number of physiological and pathological processes. Thus, it can be very important to detect the signs of apoptosis in a study of cellular metabolism. The present paper provides an overview of methods often being used for detecting DNA fragmentation as one of the most specific findings in apoptosis. To date, three routine assays have been developed for detecting DNA fragmentation: DNA ladder assay, TUNEL assay, and comet assay. All these methods differ in their principles for detecting DNA fragmentation. DNA ladder assay detects the characteristic "DNA ladder" pattern formed during internucleosomal cleavage of DNA. Terminal deoxynUcleotidyl transferase Nick-End Labeling (TUNEL) assay detects DNA strand breaks using terminal deoxynucleotidyl transferase catalyzing attachment of modified deoxynucleotides on the DNA strand breaks. Comet assay can be used for detecting nucleus breakdown producing single/double-strand DNA breaks. The aim of this review is to describe the present knowledge on these three methods, including optimized approaches, techniques, and limitations.

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WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth

Cited by 34 publications

References 27 publications

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

An overview of apoptosis assays detecting DNA fragmentation

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