Network pharmacology of triptolide in cancer cells: implications for transcription factor binding

Abstract

SummaryBackground Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10–2) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

“…The generation of cluster image maps (CIMs) or so-called heat maps was pioneered by a consortium of the Harvard Medical School, NCI (Bethesda, MD, USA), and other research institutes [ 59 , 60 ]. In the past years, we investigated this concept for natural products (e.g., [ 61 , 62 , 63 ]). Rather than transcriptomic mRNA expression, we focused on proteomics in the present investigation.…”

Triptolide restrains the growth, invasion, stemness, and glycolysis of non‐small cell lung cancer cells by PFKFB2‐mediated PI3K/AKT pathway

“…TP has been found to exert a role in cancer by targeting a variety of molecules (Seo et al., 2021). Previous studies had reported that TP inhibited breast cancer growth by targeting HMGB1 (Jiang et al., 2019).…”

Untitled

“…Most terpenoids are isolated from medicinal plants that belong to the following plant groups: Oleaceae, Rutaceae, Labiatae, Acanthaceae, Compositae, Taxaceae, Pinaceae, Lauraceae, Araliaceae, Celastraceae, etc. Terpenoids are classified according to the number of isoprene (2-methylbuta-1, 3-diene) units into monoterpenoids (C 10 ), Menthol Peppermint oil (Mentha piperita) [17] Myrcene bay laurel oil (Laurus nobilis) and Verbena oil (Lippia citriodora) [18] Perillyl alcohol [19] Eucalyptol (1.8-cineole) Eucalyptus leaf oil (Eucalyptus globules), rosemary (Rosmarinus officinalis) [20] Sesquiterpenoids Artemisinin and its derivatives Sweet wormwood (Artemisia annua) [21] Costunolide Aucklandia lappa [22,23] Diterpenoids Acanthoic acid Acanthopanax koreanum Nakai, Croton oblongifolius Roxb [24,25] Oridonin Rabdosia rubescens [26] Tanshinone IIA Salvia miltiorrhiza Bge [27] Taxol (Paclitaxel) Taxus brevifolia [28] Triptolide Tripterygium wilfordii [29,30] Kaurenoic acid Annona senegalensis (Annonaceae) [31] Triterpenoids Celastrol Tripterygium wilfordii [29] Withaferin A Withania somnifera [32] Ursolic acid Rosmarinus officinalis (rosemary), Calluna vulgaris and Eugenia jambolana, Salvia officinalis, and Eriobotrya japonica [33] Tetraterpenoids Lycopene Tomatoes (Lycopersicon esculentum), pink guavas, apricots, water melon, and pink grapefruits [34,35] Lutein Spinach, kale, carrot, corn, and egg yolk [36,37] β-carotene Carrot [38] sesquiterpenoids (C 15 ), diterpenoids (C 20 ), triterpenoids (C 30 ), tetraterpenoids (C 40 ), and polyterpenoids (C > 40) [Table 1]. They possess vast medicinal importance that includes: antitumor, antibacterial, antimalarial, anti-inflammatory, antiviral, anticancer, immunomodulatory, anti-aging, antioxidant, anti-depressants, antifungal, and antidiabetic.…”

“…Its anticancer action is by inducting mitotic arrest through the targeting of the cytoskeleton component tubulin, resulting in mitotic activation and apoptosis. [30] It is used to treat pancreatic, ovarian, and breast cancers.…”