Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database

Won, Shen‐Jeu; Wu, Hsing Chih; Lin, Kuan Ting; Yu, Chung-Huang; Chen, Yi Ting; Wu, Chi Shiuan; Huang, Chi Ying F.; Liu, Hsiao Sheng; Lin, Chun Nan; Su, Chun Li

doi:10.1016/j.jff.2015.04.025

Cited by 5 publications

(5 citation statements)

References 61 publications

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“…This highlighting that Justicidin B may act by different mechanisms depending on the cancer cell line no matter how similar they are. A robust activation of caspase-3/7 by Diphyllin methyl ether in other cell lines was similarly reported by Won et al , in human hepatoma cells [ 27 ] but other caspases have been reported to be activated in response to Diphyllin methyl ether treatment such as caspase-8 in human hepatoma Hep 3B and Hep G2 cells [ 11 ]. In addition, caspase-9 was activated in HT-29 and HCT 116 colorectal cancer cells, eventually leading to translocation of Bax from the cytosol to mitochondria to induce apoptosis [ 12 ].…”

Section: Discussionsupporting

confidence: 53%

Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375

2017

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Diphyllin and its derivatives are well known cytotoxic natural products structurally related to the anti-cancer drug podophyllotoxin. We here study their structure-activity relationship upon human melanoma cells for first time. To this end, human melanoma A375 cells were incubated with Justicidin B and its 4-methoxylated or 4-glycosylated derivatives to evaluate their selective cytotoxicity and study their effects on cell cycle distribution, caspase activation, apoptosis induction using Annexin V-FITC/PI staining, cell morphology and western blot analysis. Diphyllin methyl ether (GI50 = 3.66 μM) and Justicidin B (GI50 = 1.70 μM) caused an elevation of both early and late apoptosis populations whereas Diphyllin apioside (GI50 = 0.84 μM) and its acetate (GI50= 0.39 μM) enhanced late apoptosis population only (Annexin V-positive/PI-positive). All induced cell cycle arrest at S phase and classic morphological indicators of apoptosis (blebbing, apoptotic bodies, and nuclear fragmentation) accompanied with an elevation of cells with low DNA content (sub-G1). All compounds increased the Bax/Bcl-2 ratio by enhancing Bax expression which evidences the involvement of the mitochondria (intrinsic pathway) in the apoptotic process. These caspase-3/7 results evidence that 4-methoxylation or 4-O-glycosylation of Justicidin B -a caspase independent mitochondrial apoptosis-inducer- triggers caspase-3/7 activation at different times (24h vs. 48h, respectively). Interestingly, the methoxylation causes attenuation of Bcl-2 protein expression contrarily to Diphyllin methyl ether or the O-glycosylated derivatives. Finally, the compounds exhibited significantly less toxicity when tested in adult human dermal fibroblasts and their GI50 in melanoma Sk-Mel-5 cells was not influenced by MDR1/Pgp inhibitors. This study may inform the synthesis of future Diphyllin derivatives with different apoptosis mechanism of action towards human melanoma cells.

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Section: Discussionsupporting

confidence: 53%

Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375

2017

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“…Our novel screening platform effectively identified the molecular mechanisms of a phytochemical [33]. The gene expression profiles of cancer cells treated with or without a given phytochemical indicate which genes are up- and down-regulated by said phytochemical.…”

Section: Discussionmentioning

confidence: 99%

“…By using gene expression profiling to query LINCS, we identified the phytochemical justicidin A as an autophagy inducer [33]. Discovering and developing new drugs is not only time consuming but also costly.…”

Section: Discussionmentioning

confidence: 99%

Using the Pleiotropic Characteristics of Curcumin to Validate the Potential Application of a Novel Gene Expression Screening Platform

Liao

Hsu

Chuang³

et al. 2019

Nutrients

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Curcumin is a polyphenol derived from curcumin longa that exhibits anticancer and anti-inflammatory properties. The consumption of foods at supernutritional levels to obtain health benefits may paradoxically result in negative health outcomes. In the present study, multiple targeting characteristics of curcumin were analyzed using our gene expression screening system, which utilized the gene expression signatures of curcumin from human hepatocellular carcinoma and colorectal cancer cells to query gene expression databases and effectively identify the molecular actions of curcumin. In agreement with prediction, curcumin inhibited NF-κB and Aurora-A, and induced G2/M arrest and apoptosis. Curcumin-suppressed NF-κB was identified through inhibition of PLCG1, PIK3R1, and MALT1 in the CD4-T-cell-receptor-signaling NF-κB cascade pathway. The results suggest that our novel gene expression screening platform is an effective method of rapidly identifying unknown biological functions and side effects of compounds with potential nutraceutical benefits.

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“…Ever since the publication of CMap, 6 the LINCS library, and the commercialization of the L1000 platform, the use of highthroughput transcriptomics and query gene signatures has been successfully applied in the drug discovery and devel-opment process by a variety of research groups (For a review 24 ). In the last decade, new therapeutic targets have been found, 4,6,25,26 existing drugs have been repurposed or repositioned, 12,27,28 and side effects have been flagged. 11 To this end, a variety of similarity metrics have been proposed and their gene pattern matching success has been investigated by Cha et al 13 The connectivity score proposed by Lamb 6 and the connection approach proposed by Zhang and Gant 14 seemed…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Gene Expression Profiles to Define Drug Similarity and Predict Compound Activity

Wolf

Cougnaud²,

Hoorde³

et al. 2018

ASSAY and Drug Development Technologies

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By adding biological information, beyond the chemical properties and desired effect of a compound, uncharted compound areas and connections can be explored. In this study, we add transcriptional information for 31K compounds of Janssen's primary screening deck, using the HT L1000 platform and assess (a) the transcriptional connection score for generating compound similarities, (b) machine learning algorithms for generating target activity predictions, and (c) the scaffold hopping potential of the resulting hits. We demonstrate that the transcriptional connection score is best computed from the significant genes only and should be interpreted within its confidence interval for which we provide the stats. These guidelines help to reduce noise, increase reproducibility, and enable the separation of specific and promiscuous compounds. The added value of machine learning is demonstrated for the NR3C1 and HSP90 targets. Support Vector Machine models yielded balanced accuracy values ≥80% when the expression values from DDIT4 & SERPINE1 and TMEM97 & SPR were used to predict the NR3C1 and HSP90 activity, respectively. Combining both models resulted in 22 new and confirmed HSP90-independent NR3C1 inhibitors, providing two scaffolds (i.e., pyrimidine and pyrazolo-pyrimidine), which could potentially be of interest in the treatment of depression (i.e., inhibiting the glucocorticoid receptor (i.e., NR3C1), while leaving its chaperone, HSP90, unaffected). As such, the initial hit rate increased by a factor 300, as less, but more specific chemistry could be screened, based on the upfront computed activity predictions.

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Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database

Cited by 5 publications

References 61 publications

Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375

Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375

Using the Pleiotropic Characteristics of Curcumin to Validate the Potential Application of a Novel Gene Expression Screening Platform

High-Throughput Gene Expression Profiles to Define Drug Similarity and Predict Compound Activity

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