Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma

Walden, Daniel; Kunnimalaiyaan, Selvi; Sokolowski, Kevin M.; Gamblin, T. Clark; Kunnimalaiyaan, Muthusamy

doi:10.18632/oncotarget.21422

Cited by 26 publications

(34 citation statements)

References 31 publications

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“…Control wells were treated with DMSO. All wells were made in quadruplicate, and all plates were incubated for 48, 72, or 96 h. Cell viability was measured as described [ 25 , 26 ]. The assay was repeated at least three times.…”

Section: Methodsmentioning

confidence: 99%

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

et al. 2018

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BackgroundNeuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB. Consequently, investigating LY2090314, a clinically relevant GSK-3 inhibitor, on NB cellular proliferation and may be beneficial for NB treatment.MethodsThe effect of LY2090314 was compared with a previously studied GSK-3 inhibitor, Tideglusib. Colorimetric, clonogenic, and live-cell image confluency assays were used to study the proliferative effect of LY2090314 on NB cell lines (NGP, SK-N-AS, and SH-SY-5Y). Western blotting and caspase glo assay were performed to determine the mechanistic function of LY2090314 in NB cell lines.ResultsLY2090314 treatment exhibited significant growth reduction starting at a 20 nM concentration in NGP, SK-N-AS, and SH-SY-5Y cells. Western blot analysis indicated that growth suppression was due to apoptosis as evidenced by an increase in pro-apoptotic markers cleaved PARP and cleaved caspase-3 and a reduction in the anti-apoptotic protein, survivin. Further, treatment significantly reduced the level of cyclin D1, a key regulatory protein of the cell cycle and apoptosis. Functionally, this was confirmed by an increase in caspase activity. LY2090314 treatment reduced the expression levels of phosphorylated GSK-3 proteins and increased the stability of β-catenin in these cells.ConclusionsLY2090314 effectively reduces growth of both human MYCN amplified and non-amplified NB cell lines in vitro. To our knowledge, this is the first study to look at the effect of LY2090314 in NB cell lines. These results indicate that GSK-3 may be a therapeutic target for NB and provide rationale for further preclinical analysis using LY2090314.

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Section: Methodsmentioning

confidence: 99%

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

et al. 2018

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“…Silencing of MLK3 significantly reduces the expression of apoptotic associated proteins such as cleaved caspase‐3, cleaved PARP, Bad and Bax, as well as increasing the expression of Bcl‐2 and ratio of Bcl‐2/Bax in cardiomyocytes . Notch‐1 signalling participates in tumourigenesis, chemoresistance, cancer cell growth, and metastasis . It is elevated in organ‐specific cancers, including gynaecological malignancies .…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Notch-1 signalling participates in tumourigenesis, chemoresistance, cancer cell growth, and metastasis. 25 It is elevated in organ-specific cancers, including gynaecological malignancies. 26,27 Accumulating data has suggested that Notch-1 is implicated in autophagy and plays a critical role in cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

MLK3 silence induces cervical cancer cell apoptosis via the Notch‐1/autophagy network

Cheng

Jing³

2019

Clin Exp Pharma Physio

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Mixed‐lineage kinase 3 (MLK3), the mitogen‐activated protein kinase kinase kinase (MAP3K), has been recognized as a player in tumorigenesis and oncogenic signalling, yet its detailed functions and signalling in cervical cancer have not been fully elucidated. Here, we identify that cervical cancer cells display higher mRNA and protein levels of MLK3 than normal cervical epithelial squamous cells. In HeLa and SiHa cell, MLK3 knockdown using siRNA remarkably suppressed cell survival and promoted cell apoptosis, with increased expression of the apoptosis‐related protein Bax and reduced Bcl‐2. Moreover, MLK3 knockdown promoted cell autophagy, demonstrated by increased ratio of autophagy‐related proteins LC3II/LC3I and decreased p62 expression in MLK3 depletion cells. Furthermore, MLK3 knockdown remarkably abolished Notch‐1 expression in cervical cancer cells. By co‐treating Hela cells with MLK3 specific siRNA and pcDNA3.1‐Notch‐1 overexpression plasmid or autophagy inhibitor 3‐MA, we found that MLK3 played its role in cervical cancer cells via the Notch‐1/autophagy network. Our results demonstrate the importance of MLK3 in cervical cancer progression via modulating the Notch‐1/autophagy network, and suggest that MLK3 is a promising therapeutic target for cervical cancer.

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“…Recent studies revealed that 1 has also the ability to sensitize MCF-7/ADR cells to doxorubicin, which increases cytotoxic effect of this chemotherapy drug (Liu et al, 2017). The mechanism of anticancer activity of xanthohumol described most often involves its ability to suppress cell proliferation and induce programmed cell death in cancerous cells (Min et al, 2017;Walden et al, 2017). Xanthohumol (1) and its structural analogues are also inhibitors of many enzymes, such as cyclooxygenase and lipoxygenase, which can be involved in formation of reactive oxygen species.…”

Section: Introductionmentioning

confidence: 99%

The influence of a single and double biotinylation of xanthohumol on its anticancer activity

2019

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Two biotinylated derivatives of the main hop chalcone xanthohumol (1) were prepared by a one-step synthesis via esterification using biotin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC×HCl) and 4-dimethylaminopyridine (DMAP) as coupling reagents. The products were characterized spectroscopically and their antiproliferative activity toward MCF-7, MCF-10A, HepG2, MDA-MB-231, 4T1 and Balb/3T3 cell lines was investigated using the SRB assay. For all three tested compounds the best activity was noted in the case of human (MCF-7) and mice (4T1) breast cancer cell lines (IC50 values < 9 μM). Both biotinylated derivatives showed slightly higher anticancer activity than xanthohumol (1) towards all types of tested breast cancer cells. Double biotinylated xanthohumol (3) proved to be the most active in inhibiting cell growth, with IC50 values equal to 5.35 ± 1.5 μM for 4T1 and 8.03 ± 0.53 µM for MCF-7 cell lines. Compound 3 was also more active than 1 and 2 against liver cancer cells HepG2 (IC50 = 17.37 ± 5.1 μM), while the IC50 values for 1 and 2 were equal to 21.5 ± 2.7 and 22.1 ± 3.9 µM, respectively. 4‑O‑biotinylxanthohumol (2) was the second most active growth inhibitor, particularly with respect to MCF-7 (IC50 = 6.19 ± 1.7 μM) and 4T1 (IC50 = 6.64 ± 0.4 μM) cell lines. Our preliminary study on biotinylated xanthohumol (1) have shown that this type of functionalization is an effective method for the production of active biomolecules and study on this area should be continued thereby extending their applications.

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Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma

Cited by 26 publications

References 31 publications

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro

MLK3 silence induces cervical cancer cell apoptosis via the Notch‐1/autophagy network

The influence of a single and double biotinylation of xanthohumol on its anticancer activity

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