scholarly journals A dual-targeting ruthenium nanodrug that inhibits primary tumor growth and lung metastasis via the PARP/ATM pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu Lu ◽  
Di Zhu ◽  
Lin Gui ◽  
Yuanming Li ◽  
Wenjing Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Lung Metastasis ◽  
Dna Cleavage ◽  
Primary Tumor ◽  
Cell Cycle Progression ◽  
Chloride Ions ◽  
Lewis Lung Cancer ◽  
Dual Targeting

Abstract Background Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis. Results Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo,2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells. Conclusions Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

scholarly journals A Dual-Targeting Ruthenium Nanodrug that Inhibits Primary Tumor Growth and Lung Metastasis by the PARP/ATM Pathway

2020 ◽  
Author(s):  
Yu Lu ◽  
Di Zhu ◽  
Lin Gui ◽  
Yuanming Li ◽  
Wenjing Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Lung Metastasis ◽  
Dna Cleavage ◽  
Tumor Tissue ◽  
Chloride Ions ◽  
Inhibit Tumor Growth ◽  
Dual Targeting ◽  
Cd31 Expression

Abstract Many studies have found that ruthenium complexes have unique biochemical characteristics and thus inhibit tumor growth or metastasis. Our aim was to report a novel dual-targeting ruthenium candidate 2b with both antitumor and antimetastatic functions that could target tumor sites using both EPR effects and TF/TFR. It was composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b could trigger DNA cleavage and thus block the cell cycle and cause apoptosis by the PARP/ATM pathway. In vivo, 2b could inhibit not only LLC tumor growth but also lung metastasis. We found apoptosis and decrease in CD31 expression in tumor tissue. In addition, we also found that 2b could collect in tumor tissue. Thus, we concluded that 2b could target tumors, inhibit tumor growth and prevent lung metastasis.

scholarly journals ID: 1023 All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth

2017 ◽  
Vol 4 (S) ◽  
pp. 98
Author(s):  
P H Nguyen ◽  
J Giraud ◽  
C Staedel ◽  
L Chambonnier ◽  
P Dubus ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
3D Culture ◽  
All Trans Retinoic Acid

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-transretinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

scholarly journals TRPC1 promotes the genesis and progression of colorectal cancer via activating CaM-mediated PI3K/AKT signaling axis

Oncogenesis ◽  
2021 ◽  
Vol 10 (10) ◽  
Author(s):  
Yang Sun ◽  
Chen Ye ◽  
Wen Tian ◽  
Wen Ye ◽  
Yuan-Yuan Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Akt Signaling ◽  
Cycle Progression ◽  
Colorectal Tumorigenesis ◽  
Signaling Axis

AbstractTransient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.

Use of nanocurcumin to inhibit proliferation and metastases of hepatocellular carcinoma via NF-κB mediated matrix metalloproteinase-9 downregulation.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22103-e22103
Author(s):  
Yang Xu ◽  
Bo Hu ◽  
Robert Anders ◽  
Anirban Maitra ◽  
Jia Fan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Matrix Metalloproteinase ◽  
Tumor Growth ◽  
Cell Lines ◽  
Primary Tumor ◽  
Matrix Metalloproteinase 9 ◽  
Primary Tumor Growth ◽  
Metalloproteinase 9

e22103 Background: Curcumin regulates the expression and secretion of MMPs, and has potent anti-cancer properties in several human cancer cell lines and animal carcinogenesis models. In this study we try to investigate the effects of polymeric nanoparticle encapsulated formulation of curcumin– nanocurcumin (NC) on Hepatocellular carcinoma (HCC) in vitro and in vivo. Methods: The effects of NC alone and in combination with sorafenib (SO) were investigated on HCC cell lines, Huh7 and MHCCLM3 in vitro by using proliferation and invasion assay, western blot, qRT-PCR, enzyme-linked immunosorbent assay and immunohistochemistry staining, and the subcutaneous and orthotopic HCC xenograft nude mice models (MHCCLM3) were used to evaluate primary tumor growth and metastasis after treatments. Results: NC alone (or combined with SO)inhibited HCC cell proliferation (p<0.05) and invasion in vitro (p<0.01), and remarkably decreased both the subcutaneous and orthotopic primary tumor growth and lung metastases in vivo. NC and/or SO could down-regulating the expressions of Matrix Metalloproteinase-9 (MMP9), p-ERK1 and NF-kB/p65 (p<0.05). Conclusions: NC showed potent anti-invasion and metastasis properties in HCC via NF-κB mediated MMP9 down-regulation, which may provide a new strategy to the treatment of HCC patients and prevention of tumor recurrence after operation.

A Uracil Auxotroph Toxoplasma gondii Exerting Immunomodulation to Inhibit Breast Cancer Growth and Metastasis

2021 ◽  
Author(s):  
Li-Qing Xu ◽  
Li-Jie Yao ◽  
Dan Jiang ◽  
Min Chen ◽  
Wen-Zhong Liao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Tumor Bearing ◽  
Uracil Auxotroph ◽  
Ifn Γ

Abstract Background: Breast cancer is the most common cause of cancer-related death among women, and patients with triple-negative breast cancer (TNBC) have poor prognosis, so it is necessary to develop new effective therapies urgently. Recent studies have demonstrated that uracil auxotroph Toxoplasma gondii vaccine displays antitumor effects. Here, we examined the immunotherapy effects of an attenuated uracil auxotroph strain of T. gondii against 4T1 murine breast cancer.Methods: We constructed a uracil auxotroph strain, the orotidine 5′-monophosphate decarboxylase gene deleted strain of T. gondii (RH-Δompdc) with the CRISPR/Cas9 technology. Its virulence in vitro and in vivo was determined by parasite replication assay, plaque assay, the parasite burden detection in mice peritoneal fluids and the survival analysis of T. gondii infection mice. Its immune modulation ability was evaluated by cytokines detection. Its antitumor effect was evaluated after its in situ inoculation to 4T1 tumors in mouse model, the tumor volume was measured, the 4T1 lung metastasis was detected by H&E and Ki67 antibody staining, and the cytokines levels were measured by ELISA.Results: RH-Δompdc strain could proliferate normally with uracil supplement, however, it was unable to propagate without uracil and in vivo, which implicated that it is avirulent to the hosts. This mutant showed vaccine characteristics that it could induce intense immune responses both in vitro and in vivo by boosting the expression of inflammatory cytokines significantly. RH-Δompdc in situ inoculation to the 4T1 tumors in mice could inhibit the tumor growth, reduce the lung metastasis, promote the survival of the tumor-bearing mice, and also increase the secretion of Th1 cytokines IL-12 and IFN-γ both in serum and in the tumor microenvironment (TME). Conclusion: The uracil auxotroph RH-Δompdc inoculation to the 4T1 tumors stimulated the anti-infection and antitumor immunity in mice, resulted in the inhibition of tumor growth and metastasis, the promotion in survival of the tumor-bearing mice, and the increasing secretion of IL-12 and IFN-γ both in serum and in the TME. Our findings implied that the immunomodulation resulted by RH-Δompdc could be a potential antitumor strategy.

scholarly journals PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

2015 ◽  
Vol 2015 ◽  
pp. 1-21 ◽  
Author(s):  
Shiv Kumar ◽  
Jaebong Kim
Keyword(s):  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Wide Spectrum ◽  
Therapeutic Drug ◽  
Mitotic Kinases ◽  
Targeted Inhibitors ◽  
Si Rna

Mitotic kinases are the key components of the cell cycle machinery and play vital roles in cell cycle progression. PLK-1 (Polo-like kinase-1) is a crucial mitotic protein kinase that plays an essential role in both the onset of G2/M transition and cytokinesis. The overexpression of PLK-1 is strongly correlated with a wide spectrum of human cancers and poor prognosis. The (si)RNA-mediated depletion of PLK-1 arrests tumor growth and triggers apoptosis in cancer cells without affecting normal cells. Therefore, PLK-1 has been selected as an attractive anticancer therapeutic drug target. Some small molecules have been discovered to target the catalytic and noncatalytic domains of PLK-1. These domains regulate the catalytic activation and subcellular localization of PLK-1. However, while PLK-1 inhibitors block tumor growth, they have been shown to cause severe adverse complications, such as toxicity, neutropenia, and bone marrow suppression during clinical trials, due to a lack of selectivity and specificity within the human kinome. To minimize these toxicities, inhibitors should be tested against all protein kinasesin vivoandin vitroto enhance selectivity and specificity against targets. Here, we discuss the potency and selectivity of PLK-1-targeted inhibitors and their molecular interactions with PLK-1 domains.

scholarly journals Calmodulin 2 Facilitates Angiogenesis and Metastasis of Gastric Cancer via STAT3/HIF-1A/VEGF-A Mediated Macrophage Polarization

2021 ◽  
Vol 11 ◽  
Author(s):  
Ganggang Mu ◽  
Yijie Zhu ◽  
Zehua Dong ◽  
Lang Shi ◽  
Yunchao Deng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Macrophage Polarization ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Tubule Formation ◽  
Set Up

BackgroundTumor-associated macrophages (TAMs) are indispensable to mediating the connections between cells in the tumor microenvironment. In this study, we intended to research the function and mechanism of Calmodulin2 (CALM2) in gastric cancer (GC)-TAM microenvironment.Materials and methodsCALM2 expression in GC tissues and GC cells was determined through quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). The correlation between CALM2 level and the survival rate of GC patients was assessed. The CALM2 overexpression or knockdown model was constructed to evaluate its role in GC cell proliferation, migration, and invasion. THP1 cells or HUVECs were co-cultured with the conditioned medium of GC cells. Tubule formation experiment was done to examine the angiogenesis of endothelial cells. The proliferation, migration, and polarization of THP1 cells were measured. A xenograft model was set up in BALB/c male nude mice to study CALM2x’s effects on tumor growth and lung metastasis in vivo. Western Blot (WB) checked the profile of JAK2/STAT3/HIF-1/VEGFA in GC tissues and cells.ResultsIn GC tissues and cell lines, CALM2 expression was elevated and positively relevant to the poor prognosis of GC patients. In in-vitro experiments, CALM2 overexpression or knockdown could facilitate or curb the proliferation, migration, invasion, and angiogenesis of HUVECs and M2 polarization of THP1 cells. In in-vivo experiments, CALM2 boosted tumor growth and lung metastasis. Mechanically, CALM2 could arouse the JAK2/STAT3/HIF-1/VEGFA signaling. It was also discovered that JAK2 and HIF-1A inhibition could attenuate the promoting effects of CALM2 on GC, HUVECs cells, and macrophages.ConclusionCALM2 modulates the JAK2/STAT3/HIF-1/VEGFA axis and bolsters macrophage polarization, thus facilitating GC metastasis and angiogenesis.

scholarly journals BRD7 Promotes Cell Proliferation and Tumor Growth Through Stabilization of c-Myc in Colorectal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Ran Zhao ◽  
Yukun Liu ◽  
Chunchun Wu ◽  
Mengna Li ◽  
Yanmei Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Protein Targeting ◽  
Clinical Stage ◽  
Ubiquitin Proteasome

BRD7 functions as a crucial tumor suppressor in numerous malignancies. However, the effects of BRD7 on colorectal cancer (CRC) progression are still unknown. Here, based on the BRD7 knockout (BRD7–/–) and BRD7flox/flox (BRD7+/+) mouse models constructed in our previous work, we established an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse model. BRD7+/+ mice were found to be highly susceptible to AOM/DSS-induced colitis-associated CRC, and BRD7 significantly promoted cell proliferation and cell cycle G1/S transition but showed no significant effect on cell apoptosis. Furthermore, BRD7 interacted with c-Myc and stabilized c-Myc by inhibiting its ubiquitin–proteasome-dependent degradation. Moreover, restoring the expression of c-Myc in BRD7-silenced CRC cells restored cell proliferation, cell cycle progression, and tumor growth in vitro and in vivo. In addition, BRD7 and c-Myc were both significantly upregulated in CRC patients, and high expression of these proteins was associated with clinical stage and poor prognosis in CRC patients. Collectively, BRD7 functions as an oncogene and promotes CRC progression by regulating the ubiquitin–proteasome-dependent stabilization of c-Myc protein. Targeting the BRD7/c-Myc axis could be a potential therapeutic strategy for CRC.

scholarly journals A uracil auxotroph Toxoplasma gondii exerting immunomodulation to inhibit breast cancer growth and metastasis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Li-Qing Xu ◽  
Li-Jie Yao ◽  
Dan Jiang ◽  
Li-Juan Zhou ◽  
Min Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Bearing ◽  
Uracil Auxotroph

Abstract Background Breast cancer is the most common cause of cancer-related death among women, and prognosis is especially poor for patients with triple-negative breast cancer (TNBC); therefore, there is an urgent need for new effective therapies. Recent studies have demonstrated that the uracil auxotroph Toxoplasma gondii vaccine displays anti-tumor effects. Here, we examined the immunotherapy effects of an attenuated uracil auxotroph strain of T. gondii against 4T1 murine breast cancer. Methods We constructed a uracil auxotroph T. gondii RH strain via orotidine 5′-monophosphate decarboxylase gene deletion (RH-Δompdc) with CRISPR/Cas9 technology. The strain’s virulence in the T. gondii-infected mice was determined in vitro and in vivo by parasite replication assay, plaque assay, parasite burden detection in mice peritoneal fluids and survival analysis. The immunomodulation ability of the strain was evaluated by cytokine detection. Its anti-tumor effect was evaluated after its in situ inoculation into 4T1 tumors in a mouse model; the tumor volume was measured, and the 4T1 lung metastasis was detected by hematoxylin and eosin and Ki67 antibody staining, and the cytokine levels were measured by an enzyme-linked immunosorbent assay. Results The RH-Δompdc strain proliferated normally when supplemented with uracil, but it was unable to propagate without the addition of uracil and in vivo, which suggested that it was avirulent to the hosts. This mutant showed vaccine characteristics that could induce intense immune responses both in vitro and in vivo by significantly boosting the expression of inflammatory cytokines. Inoculation of RH-Δompdc in situ into the 4T1 tumor inhibited tumor growth, reduced lung metastasis, promoted the survival of the tumor-bearing mice and increased the secretion of Th1 cytokines, including interleukin-12 (IL-12) and interferon-γ (INF-δ), in both the serum and tumor microenvironment (TME). Conclusion Inoculation of the uracil auxotroph RH-Δompdc directly into the 4T1 tumor stimulated anti-infection and anti-tumor immunity in mice, and resulted in inhibition of tumor growth and metastasis, promotion of the survival of the tumor-bearing mice and increased secretion of IL-12 and IFN-γ in both the serum and TME. Our findings suggest that the immunomodulation caused by RH-Δompdc could be a potential anti-tumor strategy. Graphical abstract

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