scholarly journals The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Dario R. Roque ◽  
Lu Zhang ◽  
Weiya Z. Wysham ◽  
Jianjun Han ◽  
Wenchuan Sun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Dose Dependent

ObjectivesAnti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model.MethodsCell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks.ResultsNT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 μM for Ishikawa; 87 μM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice.ConclusionsNT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

scholarly journals Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Stuart R. Pierce ◽  
Ziwei Fang ◽  
Yajie Yin ◽  
Lindsay West ◽  
Majdouline Asher ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Dopamine Receptor ◽  
Therapeutic Strategy ◽  
Diet Induced Obesity ◽  
Endometrioid Endometrial Cancer

Abstract Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

scholarly journals Ophiorrhiza Pumila Extract Exhibits Tumor-suppressive Activity in a Mouse Lymphoma Model

2021 ◽  
Author(s):  
Lixia Fan ◽  
Wanqin Liao ◽  
Zezhen Chen ◽  
Shaojing Li ◽  
Anping Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Mouse Model ◽  
Tumor Growth ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Tumor Tissues

Abstract BackgroundRelapse and drug resistance of lymphomas are common, howerver the treatment efficacy of current therapeutic strategies remains unsatisfied. Our current study revealed that the extract of Ophiorrhiza pumila (OPE) has a potential anti-liver cancer activity. In this study, we aimed to investigate the effect of OPE on preventing lymphomas and explored the underlying mechanisms.MethodsCCK-8 assay was applied to detect the effect of OPE on cell proliferation. Flow cytometry was used to analyzed the effect of OPE on cell cycle distribution, and apoptosis. Xenograft mouse model was conducted to determine the anti-tumor activity of OPE. TNUEL assay was performed to detect the apoptosis in tumor tissues. Western blot and immunohistochemistry were used to determined protein expression.ResultsOPE decreased A20 cell proliferation in a dose- and time-dependent manner. OPE treatment induced cell cycle arrest at S phase and elevated apoptosis in A20 cells. Moreover, OPE displayed a significant inhibition in tumor growth in a mouse model. OPE increased apoptosis in tumor tissues revealed by TUNEL assay, which was companied with enhanced cleaved caspase 3 expression and Bax/Bcl2 ratio. In addition, our data showed that OPE suppressed A20 cell viability partially by reducing EGFR phosphorylation.ConclusionsOur data showed that OPE has an inhibitory effect on A20 cell proliferation and tumor growth, which is mediated by inactivation of EGFR and enhanced apoptosis.

SF1126, a Pan-PI3K Inhibitor Has Superior Preclinical Activity to CAL-101 a PI3K Delta-Specific Inhibitor in Aggressive B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2720-2720 ◽  
Author(s):  
Daruka Mahadevan ◽  
Wenqing Qi ◽  
Amy Stejskal ◽  
Laurence Cooke ◽  
Joseph R Garlich
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
B Cell ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Pi3k Pathway ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Abstract Abstract 2720 The PI3K pathway is constitutively active in B-cell non-Hodgkin lymphomas (B-NHL). PI3K pathway targeted therapies have focused on inhibiting mTORC1 (rapalogs) with a ∼20–48% response rate due to inactivation of mTORC1 resulting in G1 cell-cycle arrest or apoptosis. A mechanism of resistance to rapalogs is that mTORC2 is unaffected resulting in undesirable Akt activation. Strategies to block Akt up-regulation require novel agents that simultaneously block PI3K, mTORC1 and mTORC2. SF1126 is a novel pan-PI3K/mTORC1/mTORC2 inhibitor conjugated to an integrin targeted peptide RGD with potent anti-tumor activity in multiple solid tumor types. Here, we demonstrated SF1126 had potent anti-B-NHL activity and is superior to CAL-101 a PI3K delta-isoform specific inhibitor in a panel of aggressive B-NHL cell lines. Cells treated with SF1126 exhibited >90% decrease in pAkt and pGSK-3β confirming the mechanism of action of a pan-PI3K inhibitor. Moreover, SF1126 induced apoptosis in a dose and time dependent manner confirmed by flow cytometry, PARP cleavage and with an IC50 < 4μM. In contrast, CAL-101 was less active compared to SF1126 in inducing apoptosis (12% versus 25% in SUDHL-4 and 15% versus 23% in TMD-8) and cell proliferation (5.62μM versus 3.28μM SUDHL-4 and 5.31μM versus 1.47μM in TMD-8). SF1126 induced G1 cell cycle arrest at 2μM which contributes to suppression of cell proliferation. The cell cycle protein cyclin D1 is downstream of mTORC1, and the over-expression of cyclin D1 is a hallmark of mantle cell NHL (MCL). Consistent with this, cyclin D1 was significantly decreased by SF1126 compared to CAL-101. Lastly, the addition of Rituximab to SF1126 or CAL101 increased the apoptosis over single agent therapy in B-NHL cell lines. In conclusion, we demonstrate that SF1126 potently inhibits the constitutively activated PI3K/mTORC/Akt pathway in aggressive B-cell NHL cell lines with consequent suppressive effects on cell cycle progression, cell proliferation and induction of apoptosis. These findings provide a rationale for SF1126 in combination with rituximab as a novel therapeutic strategy for aggressive B-NHL and warrant early phase clinical trial evaluation [Funded by the Lymphoma SPORE 1 P50 CA 130805 01A1]. Disclosures: Garlich: Semafore Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Anti-diabetic drug metformin inhibits cell proliferation and tumor growth in gallbladder cancer via G0/G1 cell cycle arrest

2020 ◽  
Vol 31 (3) ◽  
pp. 231-240 ◽  
Author(s):  
Takuma Yamashita ◽  
Kiyohito Kato ◽  
Shintaro Fujihara ◽  
Hisakazu Iwama ◽  
Asahiro Morishita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Gallbladder Cancer ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

2021 ◽  
Author(s):  
Xia Yan ◽  
Dan Wang ◽  
Liping Zhuang ◽  
Peng Wang ◽  
Zhiqiang Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Primary Liver Cancer ◽  
Transcriptional Profiling ◽  
Cycle Arrest

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

Utilizing metformin to enhance the efficacy of androgen-deprivation therapy in the treatment of prostate cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 22-22
Author(s):  
L. Klotz ◽  
N. Venier ◽  
A. Vandersluis ◽  
R. Besla ◽  
N. Fleshner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Lines ◽  
Combination Treatment ◽  
Colony Formation ◽  
High Energy ◽  
Combination Drug

22 Background: Prostate cancer (PCa) incidence varies by geographic location, with developed countries exhibiting higher levels of disease. Some attribute this to the “Westernized lifestyle” of high energy diets and limited physical activity with consequent obesity. Obesity and related diseases like diabetes, cause hyperinsulinemia, which upregulates pro-survival insulin/insulin-like growth factor signalling. Previous work shows diet-induced hyperinsulinemia enhances PCa tumor growth in vivo. Metformin, a diabetic treatment, reduces hyperinsulinemia, and also exhibits anti-neoplastic properties. We assessed the potential benefit of combining a standard PCa treatment (bicalutamide) with metformin in vitro and in vivo. Methods: The effect of bicalutamide and/or metformin on colony formation rates was assessed in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines using clonogenic assay. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs. The combination treatment regimen was assessed in vivo using a murine xenograft model. Results: Micromolar bicalutamide or millimolar metformin caused significant dose-dependent reduction in colony formation rates (p<0.001). Combination treatment further significantly reduced colony formation rates (p<0.005). Differing mechanisms of interaction occurred in AR positive and negative cell lines. Following combination treatment LNCaP cells exhibited altered cell proliferation (decreased PCNA) and perturbed cell cycle kinetics (G1/S arrest). PC3 cells showed evidence of enhanced apoptosis (increased BAX, decreased caspase 3, phospho-Akt). Preliminary in vivo results show significantly diminished tumor growth following combination treatment (p<0.0001). Conclusions: Combining bicalutamide and metformin significantly reduces PCa cell colony formation rates further than either monotherapy. In AR positive cells this effect is mediated by reducing cell proliferation rates, whereas in AR negative cells combination treatment promotes apoptosis. This combination drug regimen may potentially improve prostate-cancer specific survival via the direct anti-neoplastic properties outlined. [Table: see text]

SRPK1 promotes cell proliferation and tumor growth of osteosarcoma through activation of the NF-κB signaling pathway

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yubao Gong ◽  
Chen Yang ◽  
Zhengren Wei ◽  
Jianguo Liu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Level ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma

Abstract To explore the expression and the functions of SRPK1 in osteosarcoma, we retrieved transcription profiling dataset by array of human bone specimens from patients with osteosarcoma from ArrayExpress (accession E-MEXP-3628) and from Gene Expression Omnibus (accession GSE16102) and analyzed expression level of SRPK1 and prognostic value in human osteosarcoma. Then we examined the effect of differential SRPK1 expression levels on the progression of osteosarcoma, including cell proliferation, cell cycle, apoptosis, and investigated its underlying molecular mechanism using in vitro osteosarcoma cell lines and in vivo nude mouse xenograft models. High expression level of SRPK1 was found in human osteosarcoma tissues and cell lines as compared to the normal bone tissues and osteoblast cells, and predicted poor prognosis of human osteosarcoma. Overexpression of SRPK1 in osteosarcoma U2OS cells led to cell proliferation but inhibition of apoptosis. In contrast, knockdown of SRPK1 in HOS cells impeded cell viability and induction of apoptosis. Moreover, silencing SRPK1 inhibited osteosarcoma tumor growth in nude mice. Mechanistic studies revealed that SRPK1 promoted cell cycle transition in osteosarcoma cells and activation of NF-κB is required for SRPK1 expression and its pro-survival signaling. SRPK1 promoted human osteosarcoma cell proliferation and tumor growth by regulating NF-κB signaling pathway.

scholarly journals The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6565
Author(s):  
Jennifer H. Foster ◽  
Eveline Barbieri ◽  
Linna Zhang ◽  
Kathleen A. Scorsone ◽  
Myrthala Moreno-Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Wild Type ◽  
Tumor Weight ◽  
Cycle Arrest ◽  
P53 Status ◽  
Neuroblastoma Cell Lines ◽  
Anti Tumor Activity

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

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