In Vitro Anticancer Effect of Gedunin on Human Teratocarcinomal (NTERA-2) Cancer Stem-Like Cells

Tharmarajah, Luxmiga; Samarakoon, Sameera Ranganath; Ediriweera, Meran Keshawa; Piyathilaka, Poorna; Tennekoon, Kamani Hemamala; Senathilake, Kanishka; Rajagopalan, Umapriyatharshini; Galhena, Prasanna; Thabrew, Ira

doi:10.1155/2017/2413197

Cited by 29 publications

(19 citation statements)

References 50 publications

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“…Booth et al described that the GRP78 inhibitor OSU-03012 in combination with sildenafil markedly reduced the HSP90 level in glioblastoma-derived (CSC-like) GBM12 cells, growing as neurospheres, and killed them [100]. Gedunin, a plant-derived compound, was found to reduce the expression of HSP90 and its client proteins in human NTERA-2 CSC-like, which that was correlated with the enhancement of apoptosis [101]. These results seem quite encouraging, although it is still unknown how the HSP90 level-reducing inhibitory treatments affect HSF1; in any case, studies in this direction should be continued.…”

Section: Targeting Intracellular Hsp90mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Targeting Intracellular Hsp90mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…The effects of gedunin on normal human cells were evaluated by WST-1 cell viability assay on human peripheral blood mononuclear cells [45]. The IC 50 value obtained was >100 µg/mL for all incubation periods tested (24,48, and 72 h), which means gedunin is not cytotoxic to these cells.…”

Section: Toxicitymentioning

confidence: 96%

“…An in silico molecular docking simulation with gedunin was carried out for its binding with receptor proteins involved in the main signaling pathways of CSCs and revealed a drug likeness of gedunin with β-catenin chain A in cancer stem cells [52]. The in vitro effectiveness of gedunin on human embryonal carcinoma (NTERA-2) cells, as a cancer stem cell model, was later evaluated, indicating a dose-and time-dependent inhibition of NTERA-2 cell proliferation treated with gedunin [45]. The compound also exerted a potential anti-proliferative effect on these cells, with IC 50 values of 14.59, 8.49, and 6.55 µg/mL at 24, 48, and 72 h after incubations, respectively.…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Biological Activities of Gedunin—A Limonoid from the Meliaceae Family

et al. 2020

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Gedunin is an important limonoid present in several genera of the Meliaceae family, mainly in seeds. Several biological activities have been attributed to gedunin, including antibacterial, insecticidal, antimalarial, antiallergic, anti-inflammatory, anticancer, and neuroprotective effects. The discovery of gedunin as a heat shock protein (Hsp) inhibitor represented a very important landmark for its application as a biological therapeutic agent. The current study is a critical literature review based on the several biological activities so far described for gedunin, its therapeutic effect on some human diseases, and future directions of research for this natural compound.

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“…Gedunin, one of the main chemical compounds in the neem tree, can protect TLR-mediated inflammation by suppression of inflammasome activation and cytokine production [169,170]. Gedunin (15 µM) suppresses EMT of pancreatic cancer by inhibiting sonic hedgehog signaling pathway [171].…”

Section: Reversal Of Emt By Anti-inflammatory Natural Compoundsmentioning

confidence: 99%

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

Lee

2019

Cancers

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Epithelial mesenchymal transition (EMT) is a key process in the progression of malignant cancer. Therefore, blocking the EMT can be a critical fast track for the development of anticancer drugs. In this paper, we update recent research output of EMT and we explore suppression of EMT by natural anti-inflammatory compounds and pro-resolving lipids.A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the m ajor signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2) belongs to the runt-related transcription factor family [19]. Runx2 plays a key role in EMT of hepatocellular carcinoma (HCC) [20]. GATA transcription factors are also implicated in the EMT of cancer cells [21].A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the major signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2...

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In Vitro Anticancer Effect of Gedunin on Human Teratocarcinomal (NTERA-2) Cancer Stem-Like Cells

Cited by 29 publications

References 50 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Biological Activities of Gedunin—A Limonoid from the Meliaceae Family

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

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