A natural acylphloroglucinol triggered antiproliferative possessions in HEL cells by impeding STAT3 signaling and attenuating angiogenesis in transgenic zebrafish model

Mi, Hu; Varier, Krishnapriya M.; Li, Zhicao; Qin, Xu‐Jie; Rao, Qing; Song, Jin‐Chao; Hu, Anling; Hang, Yubing; Yuan, Chun‐Mao; Gajendran, Babu; Shu, Liping; Wen, Min; Li, Yanmei; Liu, Haiyang

doi:10.1016/j.biopha.2021.111877

Cited by 6 publications

(8 citation statements)

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“…Our previous studies reported that the JAK-STAT signaling pathway played major roles in the carcinogenesis process. , Recent studies have demonstrated that the JAK-STAT signaling pathway is also involved in the regulation of breast cancer cell proliferation, cycle arrest, and apoptosis. , Combined with the above KEGG analysis results, we attempted to determine whether the suppressive effect of JGCs on the breast cancer cell phenotype was mediated through the JAK-STAT signaling pathway. In both MDA-MB-231 and MDA-MB-468 cells, Western blot analysis showed that JGCs could markedly decrease the expression of p -JAK2, p -STAT3, and STAT3 in a dose-dependent manner but had no effect on the expression of total JAK2 (Figure c,d).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, as shown in Figure 8b, there were many pathways potentially participating in the antitumor effects of JGCs, such as pathways in cancer (P = 1.03 × 10 Our previous studies reported that the JAK-STAT signaling pathway played major roles in the carcinogenesis process. 18,19 Recent studies have demonstrated that the JAK-STAT signaling pathway is also involved in the regulation of breast cancer cell proliferation, cycle arrest, and apoptosis. 20,21 Combined with the above KEGG analysis results, we attempted to determine whether the suppressive effect of JGCs on the breast cancer cell phenotype was mediated through the JAK-STAT signaling pathway.…”

Section: Jgcs Inhibited Breast Cancer Tumorigenesis Through the Jak2/...mentioning

confidence: 99%

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Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin’gan Capsules against Breast Cancer

Qiu

Zhang

et al. 2022

ACS Omega

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In the theory of traditional Chinese medicine (TCM), “liver-qi” stagnation and heat-induced toxicity represent the main etiologies of breast cancer. Recently, several TCMs with heat-clearing and detoxification efficacy have shown inhibitory effects on breast cancer. Jin’gan capsules (JGCs), initially approved to treat colds in China, are a heat-clearing and detoxification TCM formula. However, the anticancer activity of JGCs against breast cancer and its underlying mechanisms remain unclear. First, we assessed the antiproliferative activity of JGCs in breast cancer cell lines and evaluated their effects on cell apoptosis and the cell cycle by flow cytometry. Furthermore, we identified the potential bioactive components of JGCs and their corresponding target genes and constructed a bioactive compound–target interaction network by ultra-performance liquid chromatography–high-resolution tandem mass spectrometry (UPLC-HR-MS/MS) and network pharmacology analysis. Finally, the underlying mechanism was investigated through gene function enrichment analysis and experimental validation. We found that JGCs significantly inhibited breast cancer cell growth with IC 50 values of 0.56 ± 0.03, 0.16 ± 0.03, and 0.94 ± 0.09 mg/mL for MDA-MB-231, MDA-MB-468, and MCF-7, respectively. In addition, JGC treatment dramatically induced apoptosis and S phase cell cycle arrest in breast cancer cells. Western blot analysis confirmed that JGCs could regulate the protein levels of apoptosis- and cell cycle-related genes. Utilizing UPLC-HR-MS/MS analysis and network pharmacology, we identified 7 potential bioactive ingredients in JGCs and 116 antibreast cancer targets. Functional enrichment analysis indicated that the antitumor effects of JGCs were strongly associated with apoptosis and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Western blot analysis validated that JGC treatment markedly decreased the expression levels of p -JAK2, p -STAT3, and STAT3. Our findings suggest that JGCs suppress breast cancer cell proliferation and induce cell cycle arrest and apoptosis partly by inhibiting the JAK2/STAT3 signaling pathway, highlighting JGCs as a potential therapeutic candidate against breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Jgcs Inhibited Breast Cancer Tumorigenesis Through the Jak2/...mentioning

confidence: 99%

Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin’gan Capsules against Breast Cancer

Qiu

Zhang

et al. 2022

ACS Omega

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“…The membranes were incubated in solution with 5% milk (dissolved in TBST) at room temperature for 1 h and probed with primary antibodies and GAPDH at 4 °C overnight. After TBST washing, the membrane was developed with a secondary antibody (Hu et al, 2021). The antibodies were diluted according to the manufacturer's instructions.…”

Section: Western Blot Analysismentioning

confidence: 99%

Design, Synthesis, and Antileukemic Evaluation of a Novel Mikanolide Derivative Through the Ras/Raf/MEK/ERK Pathway

et al. 2022

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Chronic myeloid leukemia (CML) accounts for a major cause of death in adult leukemia patients due to mutations or other reasons for dysfunction in the ABL proto-oncogene. The ubiquitous BCR–ABL expression stimulates CML by activating CDK1 and cyclin B1, promoting pro-apoptotic, and inhibiting antiapoptotic marker expression along with regulations in RAS pathway activation. Thus, inhibitors of cyclins and the RAS pathway by ERK are of great interest in antileukemic treatments. Mikanolide is a sesquiterpene dilactone isolated from several Asteraceae family Mikania sp. plants. Sesquiterpene dilactone is a traditional medicine for treating ailments, such as flu, cardiovascular diseases, bacterial infections, and other blood disorders. It is used as a cytotoxic agent as well. The need of the hour is potent chemotherapeutic agents with cytotoxic effects inhibition of proliferation and activation of apoptotic machinery. Recently, ERK inhibitors are used in clinics as anticancer agents. Thus, in this study, we synthesized 22-mikanolide derivatives that elucidated to be potent antileukemic agents in vitro. However, a bioactive mikanolide derivative, 3g, was found with potent antileukemic activity, through the Ras/Raf/MEK/ERK pathway. It can arrest the cell cycle by inhibiting phosphorylation of CDC25C, triggering apoptosis, and promoting DNA and mitochondrial damage, thus suggesting it as a potential chemotherapeutic agent for leukemia patients.

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“…After 20 min, the cells were analyzed by flow cytometry (ACEA NovoCyte). [42] 4.2.5 | Cell cycle analysis Cells (1 × 10 5 cells/well) seeded into six-well plates were treated with 100, 200, and 400 nM of A2072 for 48 and 72 h. [43] Later, the collected cells were washed in PBS. Then, they were fixed in 70% ethanol at −80°C for 3 h. Later, the PBS-washed cell samples were added with 1 ml of the RNase (10 µg/ml) inhibitor, propidium iodide (100 µg/ml), and Triton X100 (0.5 µg/ml) mixture and incubated in the dark for 30 min and analyzed by flow cytometry (ACEA NovoCyte).…”

Section: Apoptosis Analysismentioning

confidence: 99%

“…The fold change of miRNA was normalized with the 2 −ΔΔCT using GAPDH. [10,43] The sequences of primers in this study are represented in Table 1.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Synthetic flavagline derivative 1‐chloroacetylrocaglaol promotes apoptosis in K562 erythroleukemia cells through miR‐17‐92 cluster genes

Yang

Varier

et al. 2022

Archiv der Pharmazie

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Chronic myeloid leukemia accounts for human deaths worldwide and could enhance sevenfold by 2050. Thus, the treatment regimen for this disorder is highly crucial at this time. Flavaglines are a natural class of cyclopentane benzofurans exhibiting various bioactivities like anticancer action. Despite the antiproliferative activity of flavaglines against diverse cancer cells, their roles and mechanism of action in chronic myeloid leukemia (CML) remain poorly understood. Thus, this study examines the antiproliferative effect of a newly synthesized flavagline derivative, 1chloracetylrocaglaol (A2074), on erythroleukemia K562 cells and the zebrafish xenograft model. The study revealed that A2074 could inhibit proliferation, promote apoptosis, and boost megakaryocyte differentiation of K562 cells. This flavagline downregulated c-MYC and miR-17-92 cluster genes, targeting upregulation of the apoptotic protein Bcl-2-like protein 11 (BIM). The work uncovered a critical role of the c-MYC-miR-17-92-BIM axis in the growth and survival of CML cells.

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A natural acylphloroglucinol triggered antiproliferative possessions in HEL cells by impeding STAT3 signaling and attenuating angiogenesis in transgenic zebrafish model

Cited by 6 publications

References 46 publications

Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin’gan Capsules against Breast Cancer

Integrating UPLC-HR-MS/MS, Network Pharmacology, and Experimental Validation to Uncover the Mechanisms of Jin’gan Capsules against Breast Cancer

Design, Synthesis, and Antileukemic Evaluation of a Novel Mikanolide Derivative Through the Ras/Raf/MEK/ERK Pathway

Synthetic flavagline derivative 1‐chloroacetylrocaglaol promotes apoptosis in K562 erythroleukemia cells through miR‐17‐92 cluster genes

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