scholarly journals Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide

2021 ◽  
Author(s):  
Takeyoshi Eda ◽  
Masayasu Okada ◽  
Ryosuke Ogura ◽  
Yoshihiro Tsukamoto ◽  
Yu Kanamaru ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dna Methyltransferase ◽  
Cultured Cells ◽  
Radiation Treatment ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Dependent Manner ◽  
Ki 67 ◽  
Mouse Xenograft Model

Multimodal therapy including surgery, radiation treatment and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to exam-ine the signal activation patterns at GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose dependent manner. These effects of on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1) positive cells within the tumor. These results suggest that CLD suppresses GBM cell growth by the inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.

scholarly journals The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-20 ◽  
Author(s):  
Xiao Liang ◽  
Chang Xu ◽  
Wanchun Wang ◽  
Xiang Li
Keyword(s):  
Dna Methyltransferase ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Mouse Xenograft Model ◽  
Human Osteosarcoma Cells ◽  
Oct4 Protein ◽  
U2os Cells ◽  
Dose Dependent

The DNA methyltransferase 1 (DNMT1)/miR-34a axis promoted carcinogenesis of various types of cancers. However, no literature reported its contribution to the stemness of osteosarcoma cancer stem-like cells (OSLCs). We sought to determine whether the DNMT1/miR-34a axis facilitates the stemness of OSLCs. We here revealed the higher DNMT1 activity and expression, lower miR-34a expression with high methylation of its promoter, and stronger stemness of OSLCs, as manifested by elevated sphere and colony formation capacities; CD133, CD44, ABCG2, Bmi1, Sox2, and Oct4 protein amounts in vitro; and carcinogenicity in a nude mouse xenograft model, when compared to the parental U2OS cells. 5-Azacytidine (Aza-dC) repressed DNMT1 activation and upregulated miR-34a expression by promoter demethylation and suppressed the stemness of OSLCs in a dose-dependent manner. DNMT1 knockdown increased miR-34a and reduced the stemness of OSLCs. Transfection with a miR-34a mimic repressed the stemness of OSLCs but did not alter DNMT1 activity and expression. Conversely, DNMT1 overexpression declined miR-34a levels, promoting the stemness of U2OS cells. Transfection with a miR-34a inhibitor enhanced the stemness of U2OS cells, without affecting the DNMT1 activity and expression. Importantly, reexpression of miR-34a could rescue the effects of DNMT1 overexpression on miR-34a inhibition as well as the stemness promotion without affecting the activity and expression of DNMT1. Our results revealed that aberrant activation of DNMT1 caused promoter methylation of miR-34a, leading to miR-34a underexpression, and the role of the DNMT1/miR-34a axis in promoting and sustaining the stemness of OSLCs.

scholarly journals MNAT1 promotes proliferation and the chemo-resistance of osteosarcoma cell to cisplatin through regulating PI3K/Akt/mTOR pathway

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chensheng Qiu ◽  
Weiliang Su ◽  
Nana Shen ◽  
Xiaoying Qi ◽  
Xiaolin Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Regulation Mechanism ◽  
Osteosarcoma Cell ◽  
Migration Ability ◽  
Mouse Xenograft Model

Abstract Background MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, highly expressed in diverse cancers and was involved in cancer molecular pathogenesis. However, its deliverance profile and biological function in osteosarcoma (OS) remain unclear. Methods The expression of MNAT1 in OS was detected by western blot (WB) and immunohistochemistry (IHC). The potential relationship between MNAT1 molecular level expression and OS clinical expectations were analyzed according to tissues microarray (TMA). Proliferation potential of OS cells was evaluated in vitro based on CCK8 and OS cells colony formation assays, while OS cells transwell and in situ tissue source wound healing assays were employed to analyze the OS cells invasion and migration ability in vitro. A nude mouse xenograft model was used to detect tumor growth in vivo. In addition, ordinary bioinformatics analysis and experimental correlation verification were performed to investigate the underlying regulation mechanism of OS by MNAT1. Results In this research, we found and confirmed that MNAT1 was markedly over-expressed in OS tissue derived in situ, also, highly MNAT1 expression was closely associated with bad clinical expectations. Functional studies had shown that MNAT1 silencing could weaken the invasion, migration and proliferation of OS cells in vitro, and inhibit OS tumor growth in vivo. Mechanism study indicated that MNAT1 contributed to the progression of OS via the PI3K/Akt/mTOR pathway. We further verified that the MNAT1 was required in the regulation of OS chemo-sensitivity to cisplatin (DDP). Conclusions Taken together, the data of the present study demonstrate a novel molecular mechanism of MNAT1 involved in the formation of DDP resistance of OS cells.

Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo

2017 ◽  
Vol 126 (5) ◽  
pp. 868-881 ◽  
Author(s):  
Wei Xing ◽  
Dong-Tai Chen ◽  
Jia-Hao Pan ◽  
Yong-Hua Chen ◽  
Yan Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Antitumor Activity ◽  
Hepg2 Cells ◽  
Xenograft Model ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Bax Protein

Abstract Background Recent epidemiologic studies have focused on the potential beneficial effects of regional anesthetics, and the differences in cancer prognosis may be the result of anesthetics on cancer biologic behavior. However, the function and underlying mechanisms of lidocaine in hepatocellular carcinoma both in vitro and in vivo have been poorly studied. Methods Human HepG2 cells were treated with lidocaine. Cell viability, colony formation, cell cycle, and apoptosis were assessed. The effects of lidocaine on apoptosis-related and mitogen-activated protein kinase protein expression were evaluated by Western blot analysis. The antitumor activity of lidocaine in hepatocellular carcinoma with or without cisplatin was investigated with in vitro experiments and also with animal experiments. Results Lidocaine inhibited the growth of HepG2 cells in a dose- and time-dependent manner. The authors also found that lidocaine arrested cells in the G0/G1 phase of the cell cycle (63.7 ± 1.7% vs. 72.4 ± 3.2%; P = 0.0143) and induced apoptosis (1.7 ± 0.3% vs. 5.0 ± 0.7%; P = 0.0009). Lidocaine may exert these functions by causing an increase in Bax protein and activated caspase-3 and a corresponding decrease in Bcl-2 protein through the extracellular signal-regulated kinase 1/2 and p38 pathways. More importantly, for the first time, xenograft experiments (n = 8 per group) indicated that lidocaine suppressed tumor development (P < 0.0001; lidocaine vs. control) and enhanced the sensitivity of cisplatin (P = 0.0008; lidocaine plus cisplatin vs. cisplatin). Conclusions The authors’ findings suggest that lidocaine may exert potent antitumor activity in hepatocellular carcinoma. Furthermore, combining lidocaine with cisplatin may be a novel treatment option for hepatocellular carcinoma.

Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood-borne malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8106-8106 ◽  
Author(s):  
M. Tesar
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Xenograft Model ◽  
Phage Display Library ◽  
Human Antibody ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Mouse Xenograft Model

8106 MOR202 is one of MorphoSys’ internal development programs targeting the cell surface antigen CD38 that is found to be expressed on various cell lines derived from B cell, T cell, and myeloid/monocytic tumors. Especially in the indication of multiple myeloma (MM), which remains an incurable malignancy with a median survival of 3–4 years, a strong expression has been reported in the majority of patients’ tumor samples. CD38-specific human antibodies were selected from MorphoSys’ proprietary HuCAL GOLD phage display library by cell panning strategies. A lead candidate (MOR202) was selected from several antibodies recognizing different epitopes on CD38 and subjected to further in vitro and in vivo characterization as follows: MOR202 exhibits an affinity in the low nanomolar range, recognizes CD38 on many cell lines of different cancer origin and most importantly on all primary MM-patient samples in FACS and IHC. The fully human IgG1 MOR202 is able to kill CD38-expressing cell lines and primary MM cells from patients efficiently by ADCC in a concentration-dependent manner, whereas early progenitor cells are not affected as demonstrated by a clonogenic assay. Finally, excellent efficacy could be shown in a SCID-mouse xenograft model, resulting in significantly reduced tumour growth (RPMI8226) and overall survival, which was even superior to bortezomib tested in the same model. No significant financial relationships to disclose.

scholarly journals A Traditional Chinese Medicine Herb Mixture Qingjie Fuzheng Granules Inhibits Hepatocellular Carcinoma Cells Growth by Inducing Apoptosis

2018 ◽  
Vol 23 ◽  
pp. 2515690X1878963 ◽  
Author(s):  
Pingping Zhong ◽  
Hong Yang ◽  
Shan Lin ◽  
Jun Peng ◽  
Jiumao Lin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Body Weight Gain ◽  
Xenograft Model ◽  
Annexin V ◽  
Nuclear Staining ◽  
Dependent Manner ◽  
Mouse Xenograft Model

In this study, hepatocellular carcinoma (HCC) mouse xenograft model, MTT assay, colony formation, nuclear staining, and Annexin-V/PI staining assays were used to evaluate the effect of Qingjie Fuzheng granules (QFG) on cell proliferation and apoptosis of HCC cell in vivo and in vitro. Furthermore, Western blotting was performed to detect the expression of Fas, FasL, Bcl-2, Bax, and the activation of caspase-3/-8/-9. The results showed that QFG reduced tumor weight ( P < .05) but had no effect on body weight gain in HCC mice in vivo. QFG significantly reduced HCC cell viability and attenuated cell proliferation in a dose-dependent manner ( P < .05). QFG increased the expression of Fas, FasL, and Bax ( P < .05). QFG downregulated the expression of Bcl-2 and promoted the activation of caspase-8, -9, and -3 ( P < .05). These results suggested that QFG possessed anticancer effects, and the mechanisms of action may involve the death receptor pathway and mitochondrion-dependent pathway-mediated apoptosis.

scholarly journals Human Schlafen 5 Inhibits Proliferation and Promotes Apoptosis in Lung Adenocarcinoma via the PTEN/PI3K/AKT/mTOR Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xuefeng Gu ◽  
Li Zhou ◽  
Lei Chen ◽  
Huiqing Pan ◽  
Rui Zhao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Immunohistochemical Analysis ◽  
Mtor Pathway ◽  
Protein Levels ◽  
Mouse Xenograft Model

Background. Human Schlafen 5 (SLFN5) is reported to inhibit or promote the proliferation of several specific types of cancer cells by our lab and other researchers. We are curious about its implications in lung adenocarcinoma (LUAC), a malignant tumor with a high incidence rate and high mortality. Method. Lentiviral stable transfections of SLFN5-specific shRNA for knockdown and SLFN5 full-length coding sequence for overexpression were performed in LUAC cell for proliferation analysis in vitro and in vivo in nude mice. Clinical LUAC samples were collected for immunohistochemical analysis of SLFN5 protein levels. Results. We found that knockdown of endogenous SLFN5 upregulates cancer cell proliferation while inhibiting apoptosis. Besides, SLFN5 inhibition on proliferation was also observed in a nude mouse xenograft model. In contrast, overexpression of exogenous SLFN5 inhibited cell proliferation in vitro and in vivo and promoted apoptosis. As to the signaling pathway, we found phosphatase and tensin homolog on chromosome 10 (PTEN) was positively regulated by SLFN5, while its downstream signaling pathway AKT/mammalian target of rapamycin (mTOR) was inhibited. Moreover, compared with adjacent normal tissues, SLFN5 protein levels were markedly decreased in lung adenocarcinoma tissues. In conclusion, these suggest that human SLFN5 plays inhibitory roles in LUAC progression through the PTEN/PI3K/AKT/mTOR pathway, providing a potential target for developing drugs for lung cancer therapy in the future.

Improved Method for Obtaining of Arctigenin from Arctium Lappa L. and its Antiproliferative Effect on Human Hepatocarcinoma HepG2 Cells

2020 ◽  
Vol 16 (3) ◽  
pp. 358-362
Author(s):  
Renan S. Teixeira ◽  
Paulo H.D. Carvalho ◽  
Jair A.K. Aguiar ◽  
Valquíria P. Medeiros ◽  
Ademar A. Da Silva Filho ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Crude Extract ◽  
Hepg2 Cells ◽  
Liver Carcinoma ◽  
Adhesion Assay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Arctium Lappa ◽  
Nih 3T3

Background: Arctigenin is a lignan found in Arctium lappa L. (Asteraceae) that displays anti-inflammatory activities. Previous studies showed that the crude extract of A. Lappa has antitumor activity in human liver carcinoma, lung and stomach cancer cells. The aim of this study was to obtain arctigenin from A. lappa L., as well as to evaluate its antiproliferative effects in cells of liver carcinoma (HepG2) and fibroblasts (NIH/3T3). Methods: Arctigenin was obtained from the hydrolysis of arctiin, which was isolated from the crude extract of A. lappa. The effects of arctigenin and arctiin on HepG2 cell viability and cell adhesion were analyzed by MTT method. Adhesion assay was also carried out to evaluate the antitumor activity. Results: Our results showed that the analytical process to obtain arctigenin was fast and easy. In vitro experiments showed that arctigenin (107-269 μM) decreased HepG2 cells viability and did not cause cytotoxicity on NIH/3T3 cells. Arctigenin (27-269 μM) demonstrated anti-adhesion in HepG2 cells in a concentration-dependent manner, when compared with control. Conclusion: These results suggest a promising pharmacological activity for arctigenin as an antiproliferative compound.

scholarly journals Synthesis and Evaluation of the Antitumor Activity of Novel 1-(4-Substituted phenyl)-2-ethyl Imidazole Apoptosis Inducers In Vitro

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4293
Author(s):  
Zhen-Wang Li ◽  
Chun-Yan Zhong ◽  
Xiao-Ran Wang ◽  
Shi-Nian Li ◽  
Chun-Yuan Pan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Antiproliferative Activity ◽  
Antitumor Agent ◽  
Positive Control ◽  
Selectivity Index ◽  
Time Dependent ◽  
Potential Candidate ◽  
Dependent Manner

Novel imidazole derivatives were designed, prepared, and evaluated in vitro for antitumor activity. The majority of the tested derivatives showed improved antiproliferative activity compared to the positive control drugs 5-FU and MTX. Among them, compound 4f exhibited outstanding antiproliferative activity against three cancer cell lines and was considerably more potent than both 5-FU and MTX. In particular, the selectivity index indicated that the tolerance of normal L-02 cells to 4f was 23–46-fold higher than that of tumor cells. This selectivity was significantly higher than that exhibited by the positive control drugs. Furthermore, compound 4f induced cell apoptosis by increasing the protein expression levels of Bax and decreasing those of Bcl-2 in a time-dependent manner. Therefore, 4f could be a potential candidate for the development of a novel antitumor agent.

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