scholarly journals Evaluation of Hedgehog Pathway Inhibitors as a Therapeutic Option for Uterine Leiomyosarcoma Using the Xenograft Model

2021 ◽  
Author(s):  
Natalia Garcia ◽  
Mara Ulin ◽  
Mohamed Ali ◽  
Ayman Al-Hendy ◽  
Katia Candido Carvalho ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Therapeutic Option ◽  
Uterine Cancer ◽  
Gynecological Cancer ◽  
Significant Proportion ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Hedgehog Pathway ◽  
Uterine Leiomyosarcoma ◽  
Potent Inhibitory Effect

AbstractUterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control (p < 0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC (p < 0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.

scholarly journals EVALUATION OF HEDGEHOG PATHWAY INHIBITORS AS A THERAPEUTIC OPTION FOR UTERINE LEIOMYOSARCOMA USING THE XENOGRAFT MODEL

2021 ◽  
Vol 116 (3) ◽  
pp. e422
Author(s):  
Natalia Garcia ◽  
Mara Ulin ◽  
Mohamed Ali ◽  
Ayman Al-Hendy ◽  
Kátia Candido Carvalho ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Xenograft Model ◽  
Hedgehog Pathway ◽  
Uterine Leiomyosarcoma

SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo

Angiogenesis ◽  
2010 ◽  
Vol 14 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Wan-Ru Chao ◽  
Khalid Amin ◽  
Yihui Shi ◽  
Peter Hobbs ◽  
Mas Tanabe ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Inhibitory Effect ◽  
Antiangiogenic Agent ◽  
Potent Inhibitory Effect

scholarly journals PIM kinases inhibit AMPK activation and promote tumorigenicity by phosphorylating LKB1

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Kwan Long Mung ◽  
William B. Eccleshall ◽  
Niina M. Santio ◽  
Adolfo Rivero-Müller ◽  
Päivi J. Koskinen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Therapeutic Option ◽  
Xenograft Model ◽  
Site Directed Mutagenesis ◽  
Breast Cancer Cell Lines ◽  
Ampk Activation ◽  
Pim Kinases ◽  
Ampk Phosphorylation

Abstract Background The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have both been implicated in the regulation of cell growth and metabolism, albeit in opposite directions. Here we investigated whether these kinases interact with each other to influence AMPK activation and tumorigenic growth of prostate and breast cancer cells. Methods We first determined how PIM and LKB1 kinases affect AMPK phosphorylation levels. We then used in vitro kinase assays to demonstrate that LKB1 is phosphorylated by PIM kinases, and site-directed mutagenesis to identify the PIM target sites in LKB1. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9 genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate and MCF7 breast cancer cell lines. In addition to cell proliferation assays, we examined the effects of PIM and/or LKB1 loss on tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. Results We provide both genetic and pharmacological evidence to demonstrate that inhibition of PIM expression or activity increases phosphorylation of AMPK at Thr172 in both PC3 and MCF7 cells, but not in their derivatives lacking LKB1. This is explained by our observation that all three PIM family kinases can phosphorylate LKB1 at Ser334. Wild-type LKB1, but not its phosphodeficient derivative, can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. In the CAM model, loss of LKB1 enhances tumorigenicity of PC3 xenografts, while cells lacking both LKB1 and PIMs exhibit slower proliferation rates and form smaller tumors. Conclusion PIM kinases are novel negative regulators of LKB1 that affect AMPK activity in an LKB1-dependent fashion. The impairment of cell proliferation and tumor growth in cells lacking both LKB1 and PIMs indicates that these kinases possess a shared signaling role in the context of cancer. These data also suggest that PIM inhibitors may be a rational therapeutic option for LKB1-deficient tumors.

scholarly journals Ultrasound-Targeted Microbubble Destruction Enhances Inhibitory Effect of Apatinib on Angiogenesis in Triple Negative Breast Carcinoma Xenografts

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dengke Hong ◽  
Jiajia Yang ◽  
Jingjing Guo ◽  
Yu Zhang ◽  
Zhikui Chen
Keyword(s):  
Body Weight ◽  
Tumor Growth ◽  
Nude Mice ◽  
Triple Negative ◽  
Good Condition ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Blood Parameters ◽  
Model Control ◽  
Growth Inhibiting

Ultrasound-targeted microbubble destruction (UTMD) has been proven as an effective technique to assist drugs to cross the vascular wall and cell membrane. This study was aimed at evaluating the synergistic antiangiogenic and growth-inhibiting effects of apatinib (APA) and UTMD on the triple negative breast cancer (TNBC). The TNBC xenograft model was established in nude mice ( n = 40 ) which were then randomly divided into the APA plus UTMD (APA-U) group, UTMD group, APA group, and model control (M) group ( n = 10 per group). Corresponding treatment was done once daily for 14 consecutive days. The general condition and body weight of tumor-bearing nude mice were monitored. Routine blood test and detection of liver and kidney function were done after treatments. The tumor size and microcirculation were examined by two-dimensional ultrasonography (2DUS) and contrast-enhanced ultrasonography (CEUS), respectively. Then, the tumor tissues were harvested for the detection of vascular endothelial growth factor (VEGF) by immunohistochemistry and for CD31-PAS double staining to assess microvessel density (MVD) and heterogeneous vascular positivity rate. After treatments, the tumor growth and angiogenesis were significantly inhibited in the APA group and the APA-U group, and these effects were more obvious in the APA-U group. The tumor volume, CEUS parameters, VEGF expression, and MVD in the APA-U group were significantly lower than those in the APA group ( P < 0.05 ), while there were no marked differences in the heterogeneous vascular positivity rate, body weight, and blood parameters between the two groups ( P > 0.05 ). In the UTMD group, the tumor growth and angiogenesis were not significantly inhibited, and all the parameters were similar to those in the M group ( P > 0.05 ). During the experiment, all mice survived and generally had good condition. In conclusion, APA combined with UTMD may exert synergistic antiangiogenic and growth-inhibiting effects on the TNBC and not increase the heterogeneous vasculature and the severity of APA-related systemic side effects.

scholarly journals High-Dose Vitamin C Tends to Kill Colorectal Cancer with High MALAT1 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Jifei Chen ◽  
Fengxian Qin ◽  
Yu Li ◽  
Shanying Mo ◽  
Kaifeng Deng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vitamin C ◽  
Tumor Growth ◽  
Cell Lines ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
High Dose ◽  
Epigenetic Alterations ◽  
Killing Effect ◽  
Implantation Metastasis

Background. Vitamin C (Vc) deficiency is frequently observed in cancer sites and has been proposed to have an antitumor effect. However, the mechanism of Vc’s killing effect is not clear. Besides, epigenetic alterations exhibit significant effects on colorectal cancer (CRC). This study aimed to explore the mechanism of Vc’s killing effect and its association to epigenetic alterations in CRC. Methods. Cell morphology, apoptosis, proliferation, and cycle were assayed to test Vc’s suppressive function in CRC cell lines. Xenograft and peritoneal implantation metastasis models were performed to evaluate the high-dose Vc’s inhibitory effect on tumor growth and metastasis. Immunohistochemistry was used to measure CD31 expression in solid tumors. A literature summary was applied for screening differently expressed long noncoding RNAs (lncRNAs) in CRC tissues and was closely associated with CRC progression. The qPCR was used to detect the expression of these lncRNAs. The association between Vc and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was evaluated in MALAT1-transfected CRC cells and a xenograft model. Results. Vc was confirmed to function in proliferation suppression, apoptosis induction, and S phase arresting in CRC cell lines. High-dose Vc, but not physiologically low-dose Vc, was identified as a suppressive function on tumor growth in xenograft models and an inhibitory effect on implantation metastasis in peritoneal implantation metastasis mice. Furthermore, a consistent downregulation of MALAT1 induced by Vc was verified among CRC cell lines and tumor tissues from both mouse models. Finally, experiments on MALAT1-knockdown CRC cells and its xenograft model suggested that Vc had a tendency in killing CRC with high MALAT1 expression. Conclusions. Our findings demonstrate that high-dose Vc has more efficiency in suppressing CRC with higher MALAT1 expression. It gives high-dose Vc the possibility of a better curative effect on CRC with overexpressed MALAT1. Further clinical studies are still needed.

scholarly journals Exosome-Transmitted lncRNA H19 Inhibits the Growth of Pituitary Adenoma

2019 ◽  
Vol 104 (12) ◽  
pp. 6345-6356 ◽  
Author(s):  
Yong Zhang ◽  
Yan Ting Liu ◽  
Hao Tang ◽  
Wan Qun Xie ◽  
Hong Yao ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Tumor Growth ◽  
Pituitary Tumor ◽  
Healthy Subjects ◽  
Noncoding Rna ◽  
Xenograft Model ◽  
Pituitary Tumors ◽  
Inhibitory Effect ◽  
Gh3 Cells ◽  
Distal Tumor

Abstract Context Our previous study demonstrated that the expression of long noncoding RNA (lncRNA) H19 was frequently downregulated in human primary pituitary adenomas and negatively correlated with tumor progression. However, the role of exosomal lncRNA H19 in the inhibition of pituitary tumor growth remains unclear. Objective To investigate whether exosomal H19 could be transported across the cell membrane to exert its inhibitory effect on pituitary tumor growth. Design Empty lentivirus GH3 cells with or without H19 overexpression were used to establish a xenograft model. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking, and Western blotting. The expression levels of serum exosomal H19 from 200 healthy subjects and 206 patients with various subtypes of pituitary tumors were detected by ultracentrifugation and quantitative real-time PCR. Results The growth of distal tumor cells was inhibited by transferring exosomal H19, which could be transported through cell membrane and exert its inhibitory effect. Cabergoline increased H19 expression and played a synergic therapeutic effect with exosomal H19. Exosomal H19 inhibited phosphorylation of the mTORC1 substrate 4E-BP1. Of note, the expression level of exosomal H19 in the patients with all subtypes of pituitary tumors was significantly lower than that in the healthy subjects. The change of plasma exosomal H19 level may be correlated with the prognosis or drug response of the patients. Conclusion Exosomal H19 inhibits the growth of distal pituitary tumors through inhibiting 4E-BP1 phosphorylation. Plasma exosomal H19 may serve as an important biomarker for predicting medical responses of patients with prolactinomas.

Inhibitory Effect of Natural Killer Cells on Liver Tumor Growth in Mouse Xenograft Model

2012 ◽  
Vol 13 (2) ◽  
pp. 157-164
Author(s):  
Ji-sung Park ◽  
◽  
Hyeran Sung ◽  
Il-Hoi Kim ◽  
Chong-Kil Lee ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Tumor Growth ◽  
Natural Killer ◽  
Liver Tumor ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Killer Cells ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

scholarly journals Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer

2017 ◽  
Vol 44 (3) ◽  
pp. 1051-1063 ◽  
Author(s):  
Hefei Wang ◽  
Bing Liu ◽  
Jing Wang ◽  
Jinglin Li ◽  
Ying Gong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Downstream Target ◽  
Colorectal Cancer Cells ◽  
Unpaired Student ◽  
Sphere Formation

Background/Aims: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. Methods: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. Results: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. Conclusion: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.

scholarly journals Crosstalk between PIM and LKB1 kinases regulates AMPK phosphorylation and tumorigenic growth

2021 ◽  
Author(s):  
Kwan Long Mung ◽  
William Eccleshall ◽  
Niina M Santio ◽  
Adolfo Rivero-Müller ◽  
Päivi J. Koskinen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Therapeutic Option ◽  
Xenograft Model ◽  
Site Directed Mutagenesis ◽  
Breast Cancer Cell Lines ◽  
Mcf7 Cells ◽  
Pim Kinases ◽  
Ampk Phosphorylation

Abstract Background The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have both been implicated in the regulation of cell growth and metabolism, albeit in opposite directions. Here we investigated whether these kinases interact with each other to influence AMPK phosphorylation and tumorigenic growth of prostate and breast cancer cells. Methods We first determined how PIM and LKB1 kinases affect AMPK phosphorylation levels. We then used in vitro kinase assays to demonstrate that LKB1 is phosphorylated by PIM kinases, and site-directed mutagenesis to identify the PIM target sites in LKB1. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9 genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate and MCF7 breast cancer cell lines. In addition to cell proliferation assays, we examined the effects of PIM and/or LKB1 loss on tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. Results We provide both genetic and pharmacological evidence to demonstrate that inhibition of PIM expression or activity increases phosphorylation of AMPK at Thr172 in both PC3 and MCF7 cells, but not in their derivatives lacking LKB1. This is explained by our observation that all three PIM family kinases can phosphorylate LKB1 at Ser334. Wild-type LKB1, but not its phosphodeficient derivative, can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. In the CAM model, loss of LKB1 enhances tumorigenicity of PC3 xenografts, while cells lacking both LKB1 and PIMs exhibit slower proliferation rates and form smaller tumors. Conclusion PIM kinases are novel negative regulators of LKB1 that affect AMPK phosphorylation in an LKB1-dependent fashion. The impairment of cell proliferation and tumor growth in cells lacking both LKB1 and PIMs indicates that there is significant crosstalk between the signaling pathways regulated by these kinases in the context of cancer. These data also suggest that PIM inhibitors may be a rational therapeutic option to restrict growth of LKB1-deficient tumors.

442: Stromal Hedgehog Pathway Activity Accelerates Prostate Tumor Growth

2006 ◽  
Vol 175 (4S) ◽  
pp. 143-143
Author(s):  
Aubie Shaw ◽  
Jerry Gipp ◽  
Wade Bushman
Keyword(s):  
Tumor Growth ◽  
Prostate Tumor ◽  
Hedgehog Pathway ◽  
Pathway Activity
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