Lanatoside C inhibits human cervical cancer cell proliferation and induces cell apoptosis by a reduction of the JAK2/STAT6/SOCS2 signaling pathway

Duan, Yu; Chen, Li; Shao, Jian Yong; Cui, Jiang; Zhao, Yang; Li, Yanyi; Ke, Huihui; Zhang, Rui; Zhu, Jianlong; Yu, Minghua

doi:10.3892/ol.2021.13001

Cited by 7 publications

(7 citation statements)

References 61 publications

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“…This effect was mediated by downregulation of the heat shock protein 90 (Hsp90)-regulated Akt/mTOR pathway in lung cancer cells [ 72 ]. Lanatoside C, a cardiac glycoside, has been shown to induce apoptosis in cancer cells by suppressing the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)/cytokine signaling (SOCS) (JAK2/STAT6/SOCS2) pathway [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells

Chaisupasakul,

Pekthong,

Wangteeraprasert

et al. 2024

PLoS ONE

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The cytotoxicity of the ethyl acetate fraction of the Calotropis gigantea (L.) Dryand. (C. gigantea) stem bark extract (CGEtOAc) has been demonstrated in many types of cancers. This study examined the improved cancer therapeutic activity of sorafenib when combined with CGEtOAc in HepG2 cells. The cell viability and cell migration assays were applied in HepG2 cells treated with varying concentrations of CGEtOAc, sorafenib, and their combination. Flow cytometry was used to determine apoptosis, which corresponded with a decline in mitochondrial membrane potential and activation of DNA fragmentation. Reactive oxygen species (ROS) levels were assessed in combination with the expression of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway, which was suggested for association with ROS-induced apoptosis. Combining CGEtOAc at 400 μg/mL with sorafenib at 4 μM, which were their respective half-IC50 concentrations, significantly inhibited HepG2 viability upon 24 h of exposure in comparison with the vehicle and each single treatment. Consequently, CGEtOAc when combined with sorafenib significantly diminished HepG2 migration and induced apoptosis through a mitochondrial-correlation mechanism. ROS production was speculated to be the primary mechanism of stimulating apoptosis in HepG2 cells after exposure to a combination of CGEtOAc and sorafenib, in association with PI3K/Akt/mTOR pathway suppression. Our results present valuable knowledge to support the development of anticancer regimens derived from the CGEtOAc with the chemotherapeutic agent sorafenib, both of which were administered at half-IC50, which may minimize the toxic implications of cancer treatments while improving the therapeutic effectiveness toward future medical applications.

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Section: Discussionmentioning

confidence: 99%

Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells

Chaisupasakul,

Pekthong,

Wangteeraprasert

et al. 2024

PLoS ONE

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“…Seventeen compounds were predicted to be apoptosis agonists, while thirteen were predicted to be Janus kinase 2 (JAK2) expression inhibitors. The activation of the JAK/STAT pathway has been proposed to induce the expression of antiapoptotic genes, potentially contributing significantly to the progression of cervical cancer tumorigenesis [115][116][117][118].…”

Section: Biological Activity Prediction Of Selected Lead Compoundsmentioning

confidence: 99%

“…Cardiac glycosides have also shown potent anticancer activities, and there is a growing interest in repurposing them for cancer treatments [177][178][179][180][181]. Lanatoside C has specifically exhibited anti-proliferative and cytotoxic effects on cervical cancer cells [118]. Lanatoside C induces apoptosis through JAK2-STAT6 signaling inhibition [118].…”

Section: Structural Similarity Search Of the Potential Candidatesmentioning

confidence: 99%

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Broni,

Ashley,

Velazquez

et al. 2024

Computation

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Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers.

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“…Three compounds, namely, ginsenoside Rb1 ( Zhang et al, 2018 ), luteolin ( Wang et al, 2020b ), and physalin D ( Ding et al, 2019 ) exhibited potential therapeutic effects on coronary artery disease, inflammation, and imbalance of macrophage polarization-related diseases. The others preferentially executed their primary role for downregulation of STAT6 signaling in the treatment of various diseases, for instance, atopic dermatitis symptoms ( Sung and Kim, 2018 ), cancer metastasis ( Yang et al, 2018 ), allergic airway inflammation ( Chen et al, 2018 ; Li et al, 2020d ), asthma ( Ma et al, 2020 ), allergic asthma ( Chen et al, 2017 ; Ma et al, 2019 ), diabetes-associated inflammation ( Oh et al, 2020 ), chronic kidney disease ( Li et al, 2020e ), cervical cancer ( Duan et al, 2021 ), inflammation ( Liu et al, 2018 ), insulin resistance ( Subash-Babu and Alshatwi, 2018 ), and AD ( Choi et al, 2020 ).…”

Section: Traditional Chinese Medicines or Herbs Or Natural Compounds ...mentioning

confidence: 99%

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling

et al. 2022

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JAK/STAT signaling pathways are closely associated with multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics. Abnormal activation of the STAT pathway can contribute to disease progressions under various conditions. Moreover, tofacitinib and baricitinib as the JAK/STAT inhibitors have been recently approved by the FDA for rheumatology disease treatment. Therefore, influences on the STAT signaling pathway have potential and perspective approaches for diverse diseases. Chinese herbs in traditional Chinese medicine (TCM), which are widespread throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas are characterized by complicated components, resulting in various targets and pathways in treating diseases, which limits their approval and applications. With the development of chemistry and pharmacology, active ingredients of TCM and herbs and underlying mechanisms have been further identified and confirmed by pharmacists and chemists, which improved, to some extent, awkward limitations, approval, and applications regarding TCM and herbs. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCM, their active compounds that treat diseases, and the underlying mechanism, further improving the rapid spread of TCM to the world.

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Lanatoside C inhibits human cervical cancer cell proliferation and induces cell apoptosis by a reduction of the JAK2/STAT6/SOCS2 signaling pathway

Cited by 7 publications

References 61 publications

Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells

Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells

Structure-Based Discovery of Potential HPV E6 and EBNA1 Inhibitors: Implications for Cervical Cancer Treatment

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling

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