scholarly journals P11.16 The stemness andinvasiveness of glioblastoma tumorspheres were suppressed by combined treatment with2’-hydroxycinnamaldehyde andtemozolomide

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii45-iii46
Author(s):  
W Kim
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Expression Profiles ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2′-hydroxycinnamaldehyde (HCA) and its derivative, 2′-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). MATERIAL AND METHODS Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

scholarly journals Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

2020 ◽  
Vol 146 (11) ◽  
pp. 2817-2828
Author(s):  
Hyeong-Cheol Oh ◽  
Jin-Kyoung Shim ◽  
Junseong Park ◽  
Ji-Hyun Lee ◽  
Ran Joo Choi ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Collagen Matrix ◽  
Human Colon ◽  
Combined Effects ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft

Abstract Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. Methods GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Results Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. Conclusion The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

scholarly journals EXTH-23. COMBINED EFFECTS OF NICLOSAMIDE AND TEMOZOLOMIDE AGAINST HUMAN GLIOBLASTOMA TUMORSPHERES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi87-vi87
Author(s):  
Hyeong Cheol Oh ◽  
Jihwan Yoo ◽  
Jin-Kyoung Shim ◽  
Junseong Park ◽  
Ji-hyun Lee ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Human Colon ◽  
Tumor Burden ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft ◽  
Related Proteins

Abstract PURPOSE Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. METHODS Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model. RESULTS The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models. CONCLUSIONS The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM. KEYWORDS: Glioblastoma; Invasion; Niclosamide; Temozolomide; Tumorsphere

scholarly journals P11.32 Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii50-iii50
Author(s):  
E Kim ◽  
H Oh ◽  
J Shim ◽  
S Kang
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Human Colon ◽  
Tumor Burden ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft ◽  
Related Proteins

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. MATERIAL AND METHODS Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model. RESULTS The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models. CONCLUSION The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

scholarly journals β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling

2019 ◽  
Vol 9 ◽  
Author(s):  
Zhang-qi Cao ◽  
Xue-xi Wang ◽  
Li Lu ◽  
Jing-wen Xu ◽  
Xiao-bin Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Combined Treatment ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Cancer Activity

β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.

scholarly journals Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Shan Xing ◽  
Zhi Tian ◽  
Wenying Zheng ◽  
Wenjuan Yang ◽  
Nan Du ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Clinical Stage ◽  
Xenograft Model ◽  
Regulatory Mechanisms ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model

Abstract Background MicroRNAs (miRNAs) show considerable promise as therapeutic agents to improve tumor treatment, as they have been revealed as crucial modulators in tumor progression. However, our understanding of their roles in gastric carcinoma (GC) metastasis is limited. Here, we aimed to identify novel miRNAs involved in GC metastasis and explored their regulatory mechanisms and therapeutic significance in GC. Methods The microRNA expression profiles of GC tumors at different stages and at different metastasis statuses were compared respectively using the stomach adenocarcinoma (STAD) miRNASeq dataset in TCGA. Using the above method, miR-4521 was picked out for further study. miR-4521 expression in GC tissues was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). Highly and lowly invasive cell sublines were established using a repetitive transwell assay. Gain-of-function and loss-of-function analyses were performed to investigate the functions of miR-4521 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Moreover, we investigated the therapeutic role of miR-4521 in a mouse xenograft model. Results In this study, we found that miR-4521 expression was downregulated in GC tissues compared with adjacent normal tissues and that its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that miR-4521 inhibited GC cell invasion and metastasis in vitro and in vivo. Further studies showed that hypoxia repressed miR-4521 expression via inducing ETS1 and miR-4521 mitigated hypoxia-mediated metastasis, while miR-4521 inactivated the AKT/GSK3β/Snai1 pathway by targeting IGF2 and FOXM1, thereby inhibiting the epithelial-mesenchymal transition (EMT) process and metastasis. In addition, we demonstrated that therapeutic delivery of synthetic miR-4521 suppressed gastric carcinoma progression in vivo. Conclusions Our results suggest an important role for miR-4521 in regulating GC metastasis and hypoxic response of tumor cells as well as the therapeutic significance of this miRNA in GC.

scholarly journals Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 739
Author(s):  
Taeju Park
Keyword(s):  
Tumor Cell ◽  
Cancer Treatment ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Therapeutic Targets ◽  
Viral Oncoprotein ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs ◽  
Cell Functions

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

scholarly journals Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Xuehua Chen ◽  
Yongquan Huang ◽  
Hui Chen ◽  
Ziman Chen ◽  
Jiaxin Chen ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Residual Tumor ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
New Paradigm ◽  
Zeolitic Imidazolate Framework ◽  
Mesenchymal Transition ◽  
Epr Effect

Abstract Background Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. Results Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. Conclusions This work provides a new paradigm for the treatment of residual HCC after IRFA. Graphical Abstract

scholarly journals Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

2011 ◽  
Author(s):  
Jessica Kandel ◽  
Dimitris Anastassiou ◽  
Viktoria Rumjantseva ◽  
Wei-yi Cheng ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Human Cancer Cells

scholarly journals Preclinical orthotopic xenograft model of renal pelvis cancer in which cancer growth could be traced by an in vivo imaging system

2018 ◽  
Vol 26 (1) ◽  
pp. 138-139 ◽  
Author(s):  
Teruki Shimizu ◽  
Masatsugu Miyashita ◽  
Atsuko Fujihara ◽  
Fumiya Hongo ◽  
Osamu Ukimura ◽  
...  
Keyword(s):  
Renal Pelvis ◽  
In Vivo Imaging ◽  
Imaging System ◽  
Xenograft Model ◽  
Cancer Growth ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model ◽  
In Vivo Imaging System

scholarly journals The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2454
Author(s):  
Cheng-Chan Yu ◽  
Sung-Ying Huang ◽  
Shu-Fang Chang ◽  
Kuan-Fu Liao ◽  
Sheng-Chun Chiu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Gelatin Zymography ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

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