Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents–A drug repurposing strategy

Wu, Chia Hsien; Li, Bai; Tsai, Ming Hsui; Chu, Pei Ming; Chiu, Chang Fang; Chen, Michael Yuanchien; Chiu, Shih Jiuan; Chiang, Jen‐Huai; Weng, Jing Ru

doi:10.1038/srep27540

Cited by 71 publications

(62 citation statements)

References 40 publications

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“…However, although we have rationally selected Trifluoperazine as an interacting ligand for NUPR1 by using biophysical and computational tools, we cannot exclude that its biological activity here reported might rely on binding to other different targets (as suggested by the results reported in Fig. 6), due to the ability of this compound to affect various tumoral pathways37. We believe that due to the inherent difficulty of proving the binding of a small molecule with a low-populated protein conformation (either in vitro or in the cell), appropriately designed cellular or in vivo phenotypic assays for assessing biological activity are a key step for detecting the interaction between the compound and its protein target.…”

Section: Discussionmentioning

confidence: 94%

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Neira

Bintz

Arruebo

et al. 2017

Sci Rep

111

138

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Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

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Section: Discussionmentioning

confidence: 94%

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Neira

Bintz

Arruebo

et al. 2017

Sci Rep

111

138

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“…Western blot analysis was performed as reported previously . Briefly, treated cells were washed with phosphate‐buffered saline (PBS), resuspended in SDS sample buffer, sonicated for 5 sec.…”

Section: Methodsmentioning

confidence: 99%

A 5′ AMP‐Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma

Weng

Dokla

et al. 2018

Basic Clin Pharma Tox

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5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment. Compound 59 induced apoptosis as indicated by caspase activation and PARP cleavage. In addition, it inhibited JAK/STAT3 signalling, arrested cells in the G1 phase, increased reactive oxygen species (ROS) generation and promoted autophagy. Interestingly, pre-treatment with a protein tyrosine phosphatase (PP2A) inhibitor, cantharidin, partially reversed compound 59-induced down-regulation of p-JAK2 and p-STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. Together, these findings substantiate the potential of compound 59 for the treatment of OSCC patients.

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“…N -acetylcysteine (NAC), a glutathione precursor for replenishing cellular glutathione storage, is a well-known reactive oxygen species (ROS) scavenger 19. NAC pretreatment can be used to investigate the role of oxidative stress dependence in drug and natural product-mediated cancer cell death 20–23. Therefore, the purpose of this study is to evaluate the role of oxidative stress in the cell-killing effects of sinuleptolide against oral cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species mediate soft corals-derived sinuleptolide-induced antiproliferation and DNA damage in oral cancer cells

Huang

Tang

Liaw

et al. 2017

OTT

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We previously reported that the soft coral-derived bioactive substance, sinuleptolide, can inhibit the proliferation of oral cancer cells in association with oxidative stress. The functional role of oxidative stress in the cell-killing effect of sinuleptolide on oral cancer cells was not investigated as yet. To address this question, we introduced the reactive oxygen species (ROS) scavenger (N-acetylcysteine [NAC]) in a pretreatment to evaluate the sinuleptolide-induced changes to cell viability, morphology, intracellular ROS, mitochondrial superoxide, apoptosis, and DNA damage of oral cancer cells (Ca9-22). After sinuleptolide treatment, antiproliferation, apoptosis-like morphology, ROS/mitochondrial superoxide generation, annexin V-based apoptosis, and γH2AX-based DNA damage were induced. All these changes were blocked by NAC pretreatment at 4 mM for 1 h. This showed that the cell-killing mechanism of oral cancer cells of sinuleptolide is ROS dependent.

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Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents–A drug repurposing strategy

Cited by 71 publications

References 40 publications

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

A 5′ AMP‐Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral Squamous Cell Carcinoma

Reactive oxygen species mediate soft corals-derived sinuleptolide-induced antiproliferation and DNA damage in oral cancer cells

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