High-Throughput Strategies for the Discovery of Anticancer Drugs by Targeting Transcriptional Reprogramming

Huang, Lijun; Xiaohong, Yi; Yu, Xiankuo; Wang, Yumei; Zhang, Chen; Qin, Lixia; Guo, Da‐Le; Zhou, Shiyi; Zhang, Guanbin; Deng, Yun; Bao, Xilinqiqige; Wang, Dong

doi:10.3389/fonc.2021.762023

Cited by 9 publications

(10 citation statements)

References 56 publications

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“…To further explore the molecular mechanisms underpinning the anti-inflammatory activity of 1 , RNA-Seq was used to generate clues about the inflammation-related signaling pathway in an unbiased manner ( Huang et al, 2021 ). In the DESeq2 step, the cut-offs of adjusted p value < 0.05 and absolute fold change ≥1.5 were applied to select differentially expressed genes (DEGs).…”

Section: Resultsmentioning

confidence: 99%

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

Kuang

Lei²,

Li³

et al. 2022

Front. Pharmacol.

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Background: Excessive inflammation results in severe tissue damage as well as serious acute or chronic disorders, and extensive research has focused on finding new anti-inflammatory hit compounds with safety and efficacy profiles from natural products. As promising therapeutic entities for the treatment of inflammation-related diseases, fusaproliferin and its analogs have attracted great interest. However, the underlying anti-inflammatory mechanism is still poorly understood and deserves to be further investigated.Methods: For the estimation of the anti-inflammatory activity of fusaproliferin (1) and its analogs (2-4)in vitro and in vivo, lipopolysaccharide (LPS)-induced RAW264.7 macrophages and zebrafish embryos were employed. Then, transcriptome analysis was applied to guide subsequent western blot analysis of critical proteins in related signaling pathways. Surface plasmon resonance assays (SPR) combined with molecular docking analyses were finally applied to evaluate the affinity interactions between 1-4 and TLR4 and provide a possible interpretation of the downregulation of related signaling pathways.Results: 1-4 significantly attenuated the production of inflammatory messengers, including nitric oxide (NO), reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the ability of compound 1 to reverse LPS stimulation and the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPKs) signaling pathways contribute to the anti-inflammatory process. Experimental verification at the protein level revealed that 1 can inhibit the activation of inhibitor of NF-κB kinase (IKK), degradation of inhibitor of NF-κB (IκB), and phosphorylation of NF-κB and reduce nuclear translocation of NF-κB. 1 also decreased the phosphorylation of MAPKs, including p38, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). SPR assays and molecular docking results indicated that 1-4 exhibited affinity for the TLR4 protein with KD values of 23.5–29.3 μM.Conclusion: Fusaproliferin and its analogs can be hit compounds for the treatment of inflammation-associated diseases.

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Section: Resultsmentioning

confidence: 99%

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

Kuang

Lei²,

Li³

et al. 2022

Front. Pharmacol.

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“…The use of LINCS L1000 project [41] in drug repositioning for immunotherapy has been already addressed [58,59]. Besides, several studies attempt to repurpose the non-human immunomodulatory peptides [60] and immunomodulatory drugs against different disorders [61].…”

Section: Discussionmentioning

confidence: 99%

Drug repositioning for immunotherapy in breast cancer using single-cell analysis

Mohammadi

Jin

Zhang

et al. 2023

Preprint

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Background: Immunomodulatory peptides are capable of stimulating or suppressing the immune system. Hence, deregulation of them can be considered as an immunotherapy approach. These peptides may have dual behavior in response to different infections. For instance, an antimicrobial peptide may act as an anticancer, tumor marker or even cause cancer progression. Methods: In this study, we used single-cell RNA sequencing analysis to investigate the deregulation of immunomodulatory peptides in malignant versus normal human breast epithelial cells. We validated the obtained results in chromatin accessibility level. Furthermore, we used a drug repositioning approach to change the expression of these peptides based on their role in cancer biology. Results: As a result, ten immunomodulatory peptides were upregulated in breast cancer versus normal. Chromatin was more accessible for these peptides in cancer cell lines versus normal. Among these ten peptides, five of them were tumor drivers (i.e., BST2, GAPDH, S100A8, S100A9 and HMGB1), three of them were anticancer (i.e., H2AFJ, SCGB2A1 and HMGN2), S100A7 had dual behavior in different cancers and ZG16B was a tumor marker. Using the LINCS L1000 database, we proposed a list of drugs that can deregulate the candidate peptides according to their role in the progression of malignancy. Conclusions: In conclusion, immunomodulatory peptides can be considered as drug targets based on their role in cancer biology.

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“…The use of LINCS L1000 project [54] in drug repositioning for immunotherapy has been already addressed [61, 62]. Besides, several studies attempt to repurpose the non-human immunomodulatory peptides [63] and immunomodulatory drugs against different disorders [64].…”

Section: Discussionmentioning

confidence: 99%

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

Mohammadi

Jin

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

Immunomodulatory peptides are capable of stimulating or suppressing the immune system. Hence, deregulation of them can be considered as an immunotherapy approach. These peptides may have dual behavior in response to different infections. For instance, an antimicrobial peptide may act as an anticancer, tumor marker or even cause cancer progression. In this study, we used single-cell RNA sequencing analysis to investigate the deregulation of immunomodulatory peptides in malignant versus normal human breast epithelial cells. We validated the obtained results in chromatin accessibility level. Furthermore, we used a drug repositioning approach to change the expression of these peptides based on their role in cancer biology. As a result, ten immunomodulatory peptides were upregulated in breast cancer versus normal. Chromatin was more accessible for these peptides in cancer cell lines versus normal. Among these ten peptides, five of them were tumor drivers (i.e., BST2, GAPDH, S100A8, S100A9 and HMGB1), three of them were anticancer (i.e., H2AFJ, SCGB2A1 and HMGN2), S100A7 had dual behavior in different cancers and ZG16B was a tumor marker. Using the LINCS L1000 database, we proposed a list of drugs that can deregulate the candidate peptides according to their role in the progression of malignancy. In conclusion, immunomodulatory peptides can be considered as drug targets based on their role in cancer biology.

show abstract

High-Throughput Strategies for the Discovery of Anticancer Drugs by Targeting Transcriptional Reprogramming

Cited by 9 publications

References 56 publications

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

Drug repositioning for immunotherapy in breast cancer using single-cell analysis

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

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