Compound Kushen Injection Protects Skin From Radiation Injury via Regulating Bim

Background: Radiation-induced skin injury is a major side-effect observed in cancer patients who received radiotherapy. Thus identifying new radioprotective drugs for prevention or treatment of post-irradiation skin injury should be prompted. A large number of clinical studies have confirmed that Compound Kushen injection (CKI) can enhance efficacy and reduce toxicity of radiotherapy. The aim of this study is to confirm the effect of CKI in alleviating radiotherapy injury in the skin and explore the exact mechanism.Methods: 60 patients who met the inclusion/exclusion criteria were allocated to treatment group (CKI before radiotherapy) or control group (normal saline before radiotherapy) randomly. MTT assay, flow cytometry, Western Blot, and transient transfection were performed to detect the cell viability, cell apoptosis and Bim expression after treatment with CKI or/and radiotherapy.Results: CKI had the effect of alleviating skin injury in cancer patients who received radiotherapy in clinic. CKI induced cancer cell apoptosis when combined with irradiation (IR), while it reversed the induction of cell apoptosis by IR in human skin fibroblast (HSF) cells. And Bim, as a tumor suppressor, was induced in cancer cells but had no change in HSF cells when treated with CKI. Moreover, the above effect could be attenuated when Bim was silenced by siRNA.Conclusion: We conclude that CKI represents a promising radio-protective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) and HSF cells (providing radio-protection via inhibiting IR-induced apoptosis), via regulating Bim. Our study uncovers a novel mechanism by which CKI inhibits human cancer cell while protects skin from radiotherapy, indicating CKI might be a promising radio-protective drug.Clinical Trial Registration: Chinese Clinical Trial Registry (www.chictr.org.cn), identifier ChiCTR2100049164.

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Preclinical studies evaluate pivotal TNFα nanomedicine clinical trial design.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14646 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14646-e14646

Author(s):

Naris Nilubol ◽

David Oarr ◽

Lawrence Tamarkin

Keyword(s):

Clinical Trial ◽

Cancer Cells ◽

Cancer Patients ◽

Cell Lines ◽

Cancer Cell ◽

Single Agent ◽

Fluid Pressure ◽

Standard Of Care ◽

Preclinical Studies ◽

Preclinical Research

e14646 Background: The clinically-tested CYT-6091 nanomedicine is comprised of TNF alpha (TNF) bound to 27 nm pegylated gold nanoparticles. Preclinical research has shown that CYT-6091 disrupts solid tumor blood vessels, reduces interstitial fluid pressure and increases accumulation of follow-on chemotherapy in the tumor microenvironment. While systemic toxicity has limited treatment of cancer patients with TNF, isolated limb perfusion of patients with in-transit melanoma using 1-4 mg of TNF followed by chemotherapy has demonstrated up to 90% complete response rates with one treatment. In a single-agent, phase I clinical study in advanced-stage cancer patients, we found that multiple CYT-6091 treatments can systemically and safely deliver up to 1.2 mg of TNF per dose. Methods: Our current research was conducted to validate administering CYT-6091 prior to standard-of-care chemotherapy in a phase II clinical trial. As part of the NCI’s Experimental Therapeutics (NExT) evaluation, CYT-6091 was studied in combination with paclitaxel (PTX) in C57BL/6 murine xenografts, using three cancer cell lines: MC-38 colon carcinoma (cancer cells sensitive to TNF, but insensitive to PTX), B16/F10 melanoma (cancer cells insensitive to TNF, but sensitive to PTX), Lewis lung carcinoma (cancer cells insensitive to both TNF and PTX), where sensitivity was based on inhibiting cancer cell growth at the studied dosing amounts and frequency. CYT-6091 was administered 3-hours before PTX, and three PTX doses were administered in each model. Results: In every model, CYT-6091 + any dose of PTX was more effective in reducing or controlling tumor growth than the highest dose of PTX alone (p < 0.01). Interestingly, we also found that CYT-6091 alone demonstrated significant anti-cancer activity (p < 0.01), suggesting that additional studies may be warranted to determine optimal frequency and dose of CYT-6091 as a single agent. Conclusions: These preclinical studies demonstrate for the first time that CYT-6091 + PTX was superior to PTX (p < 0.01) or CYT-6091 alone (P < 0.05) in TNF insensitive cell lines, which represent the majority of cancers. Findings support systemically administering CYT-6091 plus standard-of-care chemotherapy in a pivotal clinical trial.

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Effect of drug-loaded microbubbles combined with ultrasound on the apoptosis of cancer cells and the expression of Bax and Bcl-2 in a rabbit VX2 liver tumor model

Bioscience Reports ◽

10.1042/bsr20181144 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 1

Author(s):

Kun Chen ◽

Liang Zhang

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Condensation Reaction ◽

Drug Loading ◽

Mechanical Vibration ◽

B Cell Lymphoma ◽

Plga Nanoparticles ◽

Control Group ◽

Cancer Cell Apoptosis

Abstract The aim of the present study was to investigate whether the use of drug-loaded microbubbles combined with ultrasound promotes the apoptosis of cancer cells by regulating B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) expression. Adriamycin-loaded PLGA nanoparticles (ADM-NP) were fabricated using a modified emulsification process. Lipid microbubbles (NH2-MB) were prepared by mechanical vibration. The carboxyl groups of ADM-NP and NH2-MB underwent a condensation reaction after 48 h, and adriamycin-loaded PLGA nanoparticles microbubble complexes (ADM-NMC) were obtained. High-performance liquid chromatography demonstrated that the entrapment efficiency and drug loading of ADM-NMC were 85.32 ± 5.41% and 7.91 ± 0.27%, respectively. The VX2 liver cancer model was established in 30 New Zealand rabbits, which were subsequently divided into three groups (n=10): a control group that received 5 ml of saline, an ADM-NP group that received 5 ml of ADM-NP and an ADM-NMC group that received 5 ml of ADM-NMC. Rabbits in the ADM-NP and ADM-NMC groups underwent irradiation 120 s with low frequency ultrasound (1 MHz, 0.5 W/cm2) for 120 s following injection. The echogenicity of tumors markedly increased following ADM-NP and ADM-NMC treatment. Staining with hematoxylin and eosin demonstrated that the tumor shape became more normal in the ADM-NP and ADM-NMC groups compared with the control group. Immunohistochemical staining and Western blotting determined that the expression of Bax increased and the expression of Bcl-2 decreased following treatment with ADM-NP and ADM-NMC. Cancer cell apoptosis was detected by flow cytometry and it was determined that apoptosis significantly increased following treatment with ADM-NP and ADM-NMC (P<0.01). Therefore, the present study demonstrated that the use of drug-loaded microbubbles combined with ultrasound may enhance the efficiency of tumor inhibition. This may be due to the promotion of cancer cell apoptosis via regulation of Bax and Bcl-2 expression.

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Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

International Journal of Molecular Sciences ◽

10.3390/ijms22084153 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4153

Author(s):

Kutlwano R. Xulu ◽

Tanya N. Augustine

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Antiplatelet Therapy ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

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CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001033 ◽

2017 ◽

Vol 27 (7) ◽

pp. 1306-1317

Author(s):

Yen-Yun Wang ◽

Pei-Wen Hsieh ◽

Yuk-Kwan Chen ◽

Stephen Chu-Sung Hu ◽

Ya-Ling Hsu ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Cervical Cancer Cell ◽

Ros Generation ◽

Mesenchymal Transition ◽

Cervical Cancer Cells

ObjectiveThe β-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of β-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a β-nitrostyrene derivative CYT-Rx20 (3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated.MethodsThe effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, β-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo.ResultsCYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers β-catenin and Twist.ConclusionsCYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.

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ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000487286 ◽

2018 ◽

Vol 45 (3) ◽

pp. 917-934 ◽

Cited By ~ 11

Author(s):

Fangqiong Li ◽

Dongxiao Zhao ◽

Suwen Yang ◽

Juan Wang ◽

Qin Liu ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Anticancer Activity ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

A549 Cells ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

A549 Lung

Background/Aims: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood. Methods: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatography-mass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry. Results: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting. Conclusion: TP exerted anti-tumor activity on non-small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP-related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer.

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Interleukin-8 Promotes Epithelial-to-Mesenchymal Transition via Downregulation of Mir-200 Family in Breast Cancer Cells

Technology in Cancer Research & Treatment ◽

10.1177/1533033820979672 ◽

2020 ◽

Vol 19 ◽

pp. 153303382097967

Author(s):

Jin Zhang ◽

Nan Shao ◽

Xiaoyu Yang ◽

Chuanbo Xie ◽

Yawei Shi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Cancer Cell Line ◽

Control Group ◽

Mesenchymal Transition ◽

Mcf 7

The microRNA-200 (miR-200) family has been reported to be vital for the inhibition of epithelial-to-mesenchymal transition (EMT) in tumor cells. The miR-200 family represents a complex multi-factorial regulatory network which has not been well described in breast cancer. This study aimed to clarify the underlying regulatory association between IL-8 and miR-200 family in the process of EMT in breast cancer cell. In estrogen-receptor (ER) positive breast cancer cell line MCF-7, IL-8 overexpression cells were performed by lentivirus transfection as endogenous regulation with additional exogenous IL-8 stimulation. Transient overexpressions of miR-200 family were performed after endogenous or exogenous IL-8 overexpression in MCF-7 cells. IL-8 knockdown cells were constructed via siRNA and shRNA transfection in triple negative breast cancer cell line MDA-MB-231. N-cadherin, vimentin and ZEB2 were down-regulated and E-cadherin was up-regulated in IL-8 knockdown group compared with control group. On the other hand, N-cadherin, vimentin and ZEB2 were up-regulated and E-cadherin was down-regulated in IL-8 overexpression group compared with control group. This indicated IL-8 promotes EMT in breast cancer cells. Transwell assay showed that IL-8 increased the migration and invasiveness of tumor cells. Furthermore, we performed transient overexpression of miR-200 family after endogenous or exogenous IL-8 overexpression in MCF-7 cells, which showed that the miR-200 family could inhibit EMT induced by IL-8. IL-8 promoted EMT via downregulation of miR-200 family expression in breast cancer cells and increases tumor cell migration and invasion.

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Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Chemical Science ◽

10.1039/c9sc05997k ◽

2020 ◽

Vol 11 (12) ◽

pp. 3215-3222

Author(s):

Xinming Li ◽

Yanan Hou ◽

Jintao Zhao ◽

Jin Li ◽

Song Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Cancer Cell Apoptosis ◽

And Oxidative Stress

The 1,2-diselenolane unit is a general scaffold to construct glutathione-dependent prodrugs that show increased potency to cancer cells, and work via a combination of chemotherapy and oxidative stress.

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Effects of siRNA-mediated silencing of Bmi-1 gene expression on proliferation of gastric cancer cells

European Journal of Inflammation ◽

10.1177/2058739219845534 ◽

2019 ◽

Vol 17 ◽

pp. 205873921984553

Author(s):

Ying Guo ◽

Li Zhang ◽

Guangyu Zhou ◽

Qingjie Ma ◽

Shi Gao ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Flow Cytometry ◽

Cancer Cells ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Negative Control ◽

Control Group ◽

Gastric Cancer Cells ◽

Ags Cells

This study was designed to investigate the effects of siRNA-mediated silencing of Bmi-1 gene expression on proliferation of AGS gastric cancer cell. siRNA Bmi-1 was transfected into human AGS gastric cancer cells by liposome (as siRNA Bmi-1 group) with negative control (as control group); the expressions of Bmi-1 and apoptosis-related genes like P21, Bax, and Bcl-2 in AGS cells were determined by Western blot method; the apoptosis of AGS cells was detected by flow cytometry double staining and Hoechst staining; and cell cycle was measured by flow cytometry. Compared with the control group, the expression of Bmi-1 in the siRNA Bmi-1 group was significantly decreased ( P < 0.05), the apoptosis rate was increased ( P < 0.05), and cell cycles were arrested at G1 phase (P < 0.05); the expression level of P21 and Bax in cells was significantly up-regulated while that of Bcl-2 down-regulated ( P < 0.05). The down regulation of Bmi-1 can inhibit the proliferation of AGS gastric cancer cell and promote its apoptosis, which takes such effects mainly by up-regulating P21 as well as Bax and down-regulating Bcl-2.

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