scholarly journals CWHM-1008 Induces Apoptosis and Protective Autophagy through the Akt/mTOR Axis in LUAD Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jiao Zhang ◽  
Man-Yuan Li ◽  
Xiao Lu ◽  
Quan-Xing Liu ◽  
Dong Zhou ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effects ◽  
Autophagy Flux ◽  
Anticancer Properties ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Related Proteins ◽  
Antiparasitic Agents

Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.

scholarly journals HDAC6 inhibitor WT161 performs antitumor effect on osteosarcoma and synergistically interacts with 5-FU

2021 ◽  
Author(s):  
Jun Sun ◽  
Wei Wu ◽  
Xiaofeng Tang ◽  
Feifei Zhang ◽  
Cheng Ju ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Osteosarcoma Cells ◽  
Synergistic Inhibition ◽  
Proliferative Effect ◽  
Xenograft Models ◽  
Hdac6 Inhibitor ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Background: WT161, as a selective HDAC6 inhibitor, has been shown to play anti-tumor effects on several kinds of cancers. The aim of this study is to explore the roles of WT161 in osteosarcoma and its underlying mechanisms. Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were established to evaluate the anti-proliferative effect of WT161 in vivo. Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein level of PTEN and decreased the phosphorylation level of AKT. More importantly, WT161 show synergistic inhibition with 5-FU on osteosarcoma cells in vitro and in vivo. Conclusions: These results indicate that WT161 inhibits the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321386
Author(s):  
Shushu Song ◽  
Yinghong Shi ◽  
Weicheng Wu ◽  
Hao Wu ◽  
Lei Chang ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Dependent Manner ◽  
Mice Model ◽  
Calcium Dependent ◽  
B Virus ◽  
P53 Activation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

ObjectiveDysfunction of endoplasmic reticulum (ER) proteins is closely related to homeostasis disturbance and malignant transformation of hepatocellular carcinoma (HCC). Reticulons (RTN) are a family of ER-resident proteins critical for maintaining ER function. Nevertheless, the precise roles of RTN in HCC remain largely unclear. The aim of the study is to examine the effect of reticulon family member RTN3 on HCC development and explore the underlying mechanisms.DesignClinical HCC samples were collected to assess the relationship between RTN3 expression and patients’ outcome. HCC cell lines were employed to examine the effects of RTN3 on cellular proliferation, apoptosis and signal transduction in vitro. Nude mice model was used to detect the role of RTN3 in modulating tumour growth in vivo.ResultsWe found that RTN3 was highly expressed in normal hepatocytes but frequently downregulated in HCC. Low RTN3 expression predicted poor outcome in patients with HCC in TP53 gene mutation and HBV infection status-dependent manner. RTN3 restrained HCC growth and induced apoptosis by activating p53. Mechanism studies indicated that RTN3 facilitated p53 Ser392 phosphorylation via Chk2 and enhanced subsequent p53 nuclear localisation. RTN3 interacted with Chk2, recruited it to ER and promoted its activation in an ER calcium-dependent manner. Nevertheless, the tumour suppressive effects of RTN3 were abrogated in HBV-positive cells. HBV surface antigen competed with Chk2 for RTN3 binding and blocked RTN3-mediated Chk2/p53 activation.ConclusionThe findings suggest that RTN3 functions as a novel suppressor of HCC by activating Chk2/p53 pathway and provide more clues to better understand the oncogenic effects of HBV.

scholarly journals Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Tao Wang ◽  
Yanbin Gao ◽  
Rongchuan Yue ◽  
Xiaolei Wang ◽  
Yimin Shi ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Diabetic Rats ◽  
Therapeutic Effects ◽  
Ginsenoside Rg1 ◽  
Podocyte Injury ◽  
Therapeutic Function ◽  
Polymerase Chain ◽  
Underlying Mechanisms

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

Effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, on chemotherapy and antiangiogenic response in pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 243-243 ◽  
Author(s):  
Katherine T. Ostapoff ◽  
Niranjan Awasthi ◽  
Peter L. Yen ◽  
Changhua Zhang ◽  
Margaret A. Schwarz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Combination Therapy ◽  
Mtor Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Animal Experiments ◽  
Ductal Adenocarcinoma ◽  
Clinical Benefits ◽  
Induced Apoptosis

243 Background: The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathway dysregulation is a prominent feature of pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), a standard systemic treatment for PDAC, has limited clinical benefits. The present study investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Methods: Protein expression and cell proliferation were analyzed by Western blotting and WST-1 assay. Animal experiments were performed in murine xenografts. Results: BEZ235 inhibited phospho-AKT (Ser473) and phospho-mTOR (Ser2448) expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. NVP-BEZ235 also caused a significant dephosphorylation of downstream mTORC1 target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46). In vitro 72-hour proliferation of four PDAC cell lines was significantly inhibited by BEZ235. Additive effects on proliferation inhibition were observed in the BEZ235 and GEM combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with GEM and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. PDAC in vivo therapy demonstrated that compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and GEM monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235+GEM (30 days, p=0.007), BEZ235+EMAP (27 days, p=0.02), GEM+EMAP (31 days, p=0.001) and BEZ235+GEM +EMAP (33 days, p=0.004). Conclusions: BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that can be enhanced in combination with cytotoxic (GEM) and antiendothelial (EMAP) agents. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

scholarly journals Photodynamic Therapy Enhanced the Antitumor Effects of Berberine on HeLa Cells

2019 ◽  
Vol 17 (1) ◽  
pp. 413-421 ◽  
Author(s):  
Han-Qing Liu ◽  
Ya-Wen An ◽  
A-Zhen Hu ◽  
Ming-Hua Li ◽  
Guang-Hui Cui
Keyword(s):  
Photodynamic Therapy ◽  
Western Blot ◽  
Hela Cells ◽  
Mammalian Target Of Rapamycin ◽  
Control Group ◽  
Antitumor Effects ◽  
Underlying Mechanisms ◽  
And Control

AbstractIn this study we investigated the antineoplastic effects of Berberine (BBR)-mediated photodynamic therapy (PDT) on HeLa cells and its related mechanisms. The CCK-8 assay and flow cytometry were used to evaluate the proliferation and apoptosis of cells respectively. In addition, changes in protein expression levels were assessed using western blot. BBR at dose of 10 mg/kg was injected intraperitoneally to mice with tumors and PDT treatments were performed 24 hours later. In vivo imaging systems were used to evaluate the fluorescence of BBR. In vitro, PDT significantly enhanced the effects of BBR on inducing cell apoptosis and inhibiting proliferation. The in vivo results showed that the fluorescence intensity in the PDT group was decreased compared with that in the BBR group. Tumor weights and tumor size in the PDT group were less than those in the control group; however, when BBR was applied without PDT, no significant differences were observed between the BBR and control group. The results of western blot showed that PDT enhanced the inhibitory effects of BBR on the mammalian target of rapamycin (mTOR) signaling pathway, that may partly explain the potential underlying mechanisms.

The Anticancer Effect of Sanguinarine: A Review

2018 ◽  
Vol 24 (24) ◽  
pp. 2760-2764 ◽  
Author(s):  
Chenxing Fu ◽  
Guiping Guan ◽  
Hongbing Wang
Keyword(s):  
Tumor Cell ◽  
In Vivo Studies ◽  
Inhibitory Effects ◽  
Anticancer Effect ◽  
Growth Inhibitory ◽  
Cell Proliferation Inhibition ◽  
Anti Cancer ◽  
Induced Apoptosis

In vitro and in vivo studies have revealed that Sanguinarine has antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects on tumor cells of a variety of cancers. Previous research showed that sanguinarine induced apoptosis (cell death) and/or antiproliferative while reducing tumor cell antiangiogenic and anti-invasive properties. This paper describes various sanguinarine anti-cancer mechanisms, including inhibition of erroneously-activated signal transduction pathways, apoptosis, and tumor cell proliferation inhibition.

scholarly journals Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Han ◽  
Wei Guan
Keyword(s):  
Valproic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Agent ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Inhibitory Effects ◽  
Free Survival ◽  
Underlying Mechanisms

Glioma, characterized by infiltrative growth and treatment resistance, is regarded as the most prevalent intracranial malignant tumor. Due to its poor prognosis, accumulating investigation has been performed for improvement of overall survival (OS) and progression-free survival (PFS) in glioma patients. Valproic acid (VPA), one of the most common histone deacetylase inhibitors (HDACIs), has been detected to directly or synergistically exert inhibitory effects on glioma in vitro and in vivo. In this review, we generalize the latest advances of VPA in treating glioma and its underlying mechanisms and clinical implications, providing a clearer profile for clinical application of VPA as a therapeutic agent for glioma.

Anti-Angiongenic Effects of mTOR-Inhibitors Is Regulated by AKT Activity in Multiple Myeloma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3406-3406
Author(s):  
Patrick Frost ◽  
Bao Hoang ◽  
Yijiang Shi ◽  
Huajun Yan ◽  
Alan Lichtenstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Mtor Inhibitors ◽  
Underlying Mechanisms ◽  
Salvage Pathways

Abstract Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin (RAPA) and CCI-779 (CCI), have potential as anti-tumor agents against multiple myeloma (MM). Since other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors, we stably transfected U266 human MM cells with a constitutively activated AKT allele (U266-AKT) or empty vector control (U266-EV) in order to further explore the underlying mechanisms of this phenomena. Analysis of cell death demonstrated that U266-AKT were significantly more sensitive to RAPA in vitro, with an ED50 of 0.01 nM versus an ED50 of >100 nM for U266-EV control cells. A similar alteration of sensitivity to CCI was demonstrated in U266 isogenic tumors grown in NOD/SCID mice and treated with CCI in vivo. Analysis of the excised tumor nodules demonstrated a >5 fold inclease in apoptotic nuclei in U266-AKT tumors treated with CCI compared to isogenic control tumors, despite previous reports that mTOR inhibitors do not induce apoptosis in MM cells in vitro. One potential explanation for this is that AKT regulates the ability of CCI to inhibit angiogenesis, which is only relevent in vivo, and thereby indirectly induces apoptotic cell death. In support of this hypothesis, we demonstrated that CCI significantly decreased angiogenesis (measued by in situ staining of excised tumor nodules with CD34, a marker for endothelial cells) by 80% in U266-AKT, and only by 67% in isogenic controls. Since previous studies demonstrated that AKT/mTOR regulates the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1a (HIF1a), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-mediated inhibition of these critical angiogenic factors. In vitro, RAPA was markedly more effective at inhibiting HIF-1a and VEGF expression from U266-AKT compared to U266-EV control cells. One possible explanation for the regulatory role of AKT in the RAPA/CCI response is that MM cells with hyperactive AKT function depend upon mTOR-mediated (i.e. cap-dependent) translational pathway to express critical proteins like VEGF and HIF-1a, while “low-AKT” MM cells may be able to utilize non-mTOR dependent (i.e. cap-independent) salvage pathways to express these critical proteins and are thereby resistant to mTOR inhibitors.

scholarly journals Downregulation of B7-H4 suppresses tumor progression of hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lijie Dong ◽  
Lulu Xie ◽  
Minjing Li ◽  
Hanhan Dai ◽  
Xia Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mr Images ◽  
Caspase 7 ◽  
Adc Values ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Related Proteins ◽  
Proliferation And Migration

Abstract B7-H4, as a member of the B7 superfamily, was overexpressed in various types of cancers. However, the effects of B7-H4 on the aggressiveness of HCC and the underlying mechanisms have not yet been fully explored. For this purpose, B7-H4 expression was detected by Flow cytometry and Western blotting, it was highly expressed in several HCC cell lines but not in normal LO2 cell line. Knockdown B7-H4 expression induced HCC cells apoptosis by flow cytometry and colony formation assays and increased several apoptosis-related proteins, including survivin, cleaved caspase-3, cleaved caspase-7, and Bax, while the pro-growth protein survivin was reduced. Then the proliferation and cell cycle were suppressed after treated by siB7-H4. Moreover, the level of B7-H4 was significantly correlated with cell migration. In vivo, intra-tumor injection of siRNA targeting B7-H4 can significantly inhibited the growth of HepG2 cells in nude mice. Finally, regions of interest were manually traced on T1WI, T2WI, DWI and ADC of MR images. ADC values were increased in HCC xenografts after B7-H4 siRNA treatment. These data indicated that downregulation of B7-H4 suppressed the proliferation and migration and promoted apoptosis in vitro and in vivo. Blocking the B7-H4 channel might be a potential therapeutic strategy for HCC.

scholarly journals Anticancer Properties and Mechanisms of Singly-Protonated Dehydronorcantharidin Silver Coordination Polymer in a Bladder Cancer Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Changkuo Zhou ◽  
Ganyu Wang ◽  
Weiqiang Jing ◽  
Xuejie Tan ◽  
Hu Guo
Keyword(s):  
Bladder Cancer ◽  
Protein Levels ◽  
Anticancer Properties ◽  
G1 Phase Arrest ◽  
Bladder Cancer Cells ◽  
System Tumor ◽  
Induced Apoptosis ◽  
Effective Drugs

Bladder cancer is the most common malignant urinary system tumor. Chemotherapy is frequently used as a treatment regimen for patients with bladder cancer, however, new and effective drugs for bladder cancer need to be developed. The present study examined the effects and mechanisms of Ag-SP-DNC, a silver and singly-protonated dehydronorcantharidin complex, on bladder cancer in vitro and in vivo. It was identified that Ag-SP-DNC suppressed cell proliferation and induced apoptosis in bladder cancer cells in vitro, a suppression associated with G0/G1 phase arrest and elevated intracellular reactive oxygen species (ROS) levels. Furthermore, Ag-SP-DNC enhanced the cleaved caspase-3 levels, disrupted the mitochondrial transmembrane potential balance, and induced intracellular calcium overload. The Ag-SP-DNC-induced bladder cancer cell apoptosis was significantly decreased following treatment with a broad caspase inhibitor, zVAD-fmk. In addition, treatment of MB49 tumor-bearing mice with Ag-SP-DNC significantly inhibited tumor growth and decreased the anti-apoptosis and cell cycle promotion protein levels in the tumor. The results of the present study suggested that Ag-SP-DNC elicits a strong anticancer effect against bladder cancer, and can therefore be used as a promising treatment for bladder cancer.

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