scholarly journals Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1581 ◽  
Author(s):  
Damien Reita ◽  
Cyril Bour ◽  
Radhia Benbrika ◽  
Audrey Groh ◽  
Erwan Pencreach ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lung Metastases ◽  
Mammalian Target Of Rapamycin ◽  
Decisive Role ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Low Doses ◽  
Antitumor Effects ◽  
Colon Cell

Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and it is known that new mammalian target of rapamycin (mTOR) catalytic AZD inhibitors, unlike rapamycin, target both mTORC1 and mTORC2. Thus, we hypothesized that the complete inhibition of the PI3K/AKT/mTOR/HIF-1α axis with mTOR catalytic inhibitors and low doses of irinotecan may have antitumor effects. We showed that the AZD8055 and AZD2014 inhibitors were much more potent than rapamycin to reduce cell viability of four colon cell lines. On the other hand, whereas AZD2014 alone inhibits migration by 40%, the drug combination led to 70% inhibition. Similarly, neither irinotecan nor AZD2014 significantly reduced cell invasion, whereas a combination of the two inhibits invasion by 70%. In vivo, irinotecan and AZD2014 combination drastically reduced ectopic patient-derived colon tumor growth and this combination was more potent than Folfox or Folfiri. Finally, the combination totally inhibited liver and lung metastases developed from orthotopic implantation of SW480 cells. Thus, the use of mTOR catalytic inhibitors, in association with other chemotherapeutic agents like irinotecan at low doses, is potentially a hope for colon cancer treatment.

scholarly journals Inhibition of the mTORC2 and chaperone pathways to treat leukemia

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6080-6088 ◽  
Author(s):  
Fan Zhang ◽  
Adam S. Lazorchak ◽  
Dou Liu ◽  
Fangping Chen ◽  
Bing Su
Keyword(s):  
Cell Growth ◽  
Mammalian Target Of Rapamycin ◽  
Leukemia Cell ◽  
Mtor Inhibitors ◽  
Hsp90 Inhibitor ◽  
Human Leukemia ◽  
Antitumor Effects ◽  
Chaperone Protein ◽  
The Stability

Abstract Constitutive activation of the kinases Akt or protein kinase C (PKC) in blood cancers promotes tumor-cell proliferation and survival and is associated with poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) regulates the stability of Akt and conventional PKC (cPKC; PKCα and PKCβ) proteins by phosphorylating the highly conserved turn motif of these proteins. In cells that lack mTORC2 function, the turn motif phosphorylation of Akt and cPKC is abolished and therefore Akt and cPKC protein stability is impaired. However, the chaperone protein HSP90 can stabilize Akt and cPKC, partially rescuing the expression of these proteins. In the present study, we investigated the antitumor effects of inhibiting mTORC2 plus HSP90 in mouse and human leukemia cell models and show that the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) preferentially inhibits Akt and cPKC expression and promotes cell death in mTORC2 deficient pre-B leukemia cells. Furthermore, we show that 17-AAG selectively inhibits mTORC2 deficient leukemia cell growth in vivo. Finally, we show that the mTOR inhibitors rapamycin and pp242 work together with 17-AAG to inhibit leukemia cell growth to a greater extent than either drug alone. These studies provide a mechanistic and clinical rationale to combine mTOR inhibitors with chaperone protein inhibitors to treat human blood cancers.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

2008 ◽  
Vol 10 ◽  
Author(s):  
Elias Drakos ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Central Element ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Mtor Inhibition

AbstractThe mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

scholarly journals Combinatorial Treatment with mTOR Inhibitors and Streptozotocin Leads to Synergistic In Vitro and In Vivo Antitumor Effects in Insulinoma Cells

2017 ◽  
Vol 17 (1) ◽  
pp. 60-72 ◽  
Author(s):  
Julien Bollard ◽  
Céline Patte ◽  
Patrick Massoma ◽  
Isabelle Goddard ◽  
Nicolas Gadot ◽  
...  
Keyword(s):  
Mtor Inhibitors ◽  
Antitumor Effects ◽  
Insulinoma Cells ◽  
Combinatorial Treatment

scholarly journals {Ru(CO)x}-Core complexes with benzimidazole ligands: synthesis, X-ray structure and evaluation of anticancer activity in vivo

2017 ◽  
Vol 46 (9) ◽  
pp. 3025-3040 ◽  
Author(s):  
Gabriella Tamasi ◽  
Antonello Merlino ◽  
Federica Scaletti ◽  
Petra Heffeter ◽  
Anton A. Legin ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Anticancer Activity ◽  
Antitumor Effects ◽  
X Ray ◽  
Murine Colon

fac-[RuII(CO)3Cl2(MBI)] and -[RuII(CO)3Cl2(DMBI)] are CO-releasing materials able to link histidines of proteins, and the latter showed antitumor effects in murine colon cancer.

scholarly journals Blocking AMPK/ULK1-dependent autophagy promoted apoptosis and suppressed colon cancer growth

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jing Liu ◽  
Shuaiyu Long ◽  
Huanan Wang ◽  
Nannan Liu ◽  
Chuchu Zhang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Therapeutic Option ◽  
Tumor Xenograft ◽  
Cancer Growth ◽  
Antitumor Effects ◽  
Obvious Effect ◽  
Evolutionarily Conserved ◽  
Induced Apoptosis

Abstract Background Autophagy is an evolutionarily conserved process through which cells degrade and recycle cytoplasm. The relation among autophagy, apoptosis and tumor is highly controversial until now and the molecular mechanism is poorly understood. Methods Cell viability and apoptosis were detected by CCK8, crystal violet staining, Hoechst333342 staining and flow cytometry. The expression of AMPK and ULK1 was analyzed by western blotting. Colon cancer growth suppression by NVP-BEZ235 or CQ in vivo was studied in a tumor xenograft mouse model. Results Our previous study revealed that NVP-BEZ235 suppressed colorectal cancer growth via inducing apoptosis, however later, we found it also initiated autophagy simultaneously. In this present study, our results show that NVP-BEZ235 induced autophagy through AMPK/ULK1 pathway in colon cancer cells. Blocking autophagy by knocking down AMPK or ULK1 inhibited cell proliferation and further promoted NVP-BEZ235 induced apoptosis. Meantime, the autophagy inhibitor chloroquine (CQ) shows obvious effect on inhibiting cell proliferation but not on inducing apoptosis, while it significantly increased NVP-BEZ235 induced apoptosis. Furthermore, the combinational therapy of NVP-BEZ235 and CQ shows synergistic antitumor effects in colon cancer in vivo. Conclusion NVP-BEZ235 induced AMPK/ULK1-dependent autophagy. Targeting this autophagy suppressed colon cancer growth through further promoting apoptosis, which is a potential therapeutic option for clinical patients.

scholarly journals Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand

2020 ◽  
Author(s):  
Junhui Yu ◽  
Kui Yang ◽  
Jianbao Zheng ◽  
Wei Zhao ◽  
Xuejun Sun
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Farnesoid X Receptor ◽  
Colon Cancer Cells ◽  
Antitumor Effects ◽  
Colorectal Tumorigenesis ◽  
Tumor Inhibition ◽  
Combination Study

Abstract The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.

scholarly journals Inhibitory Effects of Apigenin on Tumor Carcinogenesis by Altering the Gut Microbiota

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shichang Bian ◽  
Hongjuan Wan ◽  
Xinyan Liao ◽  
Weisheng Wang
Keyword(s):  
Colon Cancer ◽  
Treatment Group ◽  
16S Rrna ◽  
Gut Microbiota ◽  
High Throughput Sequencing ◽  
Potential Mechanism ◽  
Inhibitory Effects ◽  
Antitumor Effects

The flavonoid apigenin is common to many plants. Although the responsible mechanisms have yet to be elucidated, apigenin demonstrates tumor suppression in vitro and in vivo. This study uses an azoxymethane (AOM)/dextran sodium sulfate- (DSS-) induced colon cancer mouse model to investigate apigenin’s potential mechanism of action exerted through its effects upon gut microbiota. The size and quantity of tumors were reduced significantly in the apigenin treatment group. Using 16S rRNA high-throughput sequencing of fecal samples, the composition of gut microbiota was significantly affected by apigenin. Further experiments in which gut microbiota were reduced and feces were transplanted provided further evidence of apigenin-modulated gut microbiota exerting antitumor effects. Apigenin was unable to reduce the number or size of tumors when gut microbiota were depleted. Moreover, tumor inhibition effects were initiated following the transplant of feces from mice treated with apigenin. Our findings suggest that the effect of apigenin on the composition of gut microbiota can suppress tumors.

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.

scholarly journals The Interleukin-17 Family of Cytokines in Breast Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3880 ◽  
Author(s):  
Joseph Fabre ◽  
Jérôme Giustiniani ◽  
Christian Garbar ◽  
Yacine Merrouche ◽  
Frank Antonicelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Interleukin 17 ◽  
Cyclin Dependent Kinase ◽  
Antitumor Effects ◽  
Phase 3 ◽  
Research Teams ◽  
Checkpoint Proteins ◽  
Standard Management

Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.

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