Gemcitabine and carboplatin demonstrate synergistic cytotoxicity in cervical cancer cells by inhibiting DNA synthesis and increasing cell apoptosis

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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Synergistic Cytotoxicity Effect of 5-fluorouracil and SHP2 Inhibitor Demethylincisterol A3 on Cervical Cancer Cell

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210708130703 ◽

2021 ◽

Vol 21 ◽

Author(s):

Yang Liu ◽

Hua Fu ◽

Li Zuo

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cytotoxic Effect ◽

Signalling Pathways ◽

Combined Effects ◽

Cytotoxic Effects ◽

Promising Strategy ◽

Synergistic Cytotoxicity ◽

Cervical Cancer Cells ◽

Synergistic Cytotoxic Effect

Background: Demethylincisterol A3 (DTA3) has been identified as an SHP2 inhibitor and suppresses the growth of many cancer cells. 5-Fluorouracil (5-FU) is widely used for the clinical treatment of various cancers. However, the combined effects of 5-FU and DTA3 on cervical cancer cells remain unknown. Objective: his study evaluates the mechanism of the combined effects of 5-FU and DTA3 in cervical cancer cells. Methods: The synergistic cytotoxic effects of 5-FU and DTA3 in cervical cancer cells were calculated. Apoptosis was analysed by flow cytometry. Western blot analyses were used to examine the related signalling pathways. Results: DTA3 and 5-FU synergized to induce apoptosis and repress proliferation of cervical cancer cells by downregulating the activation of PI3K/AKT and NF-κB signalling pathway. We provided evidence that the upregulation of SHP2 expression by transfection significantly inhibited the cytotoxicity of 5-FU and DTA3. SHP2 knockdown enhanced the antiproliferation activity of 5-FU, indicating targeting SHP2 sensitized cervical cancer cells to 5-FU. Conclusion: Our study demonstrates that SHP2 inhibitor DTA3 and 5-FU have a synergistic cytotoxic effect on cervical cancer cells. The synergistic combination of SHP2 inhibitor and 5-FU may present a promising strategy for the treatment of cervical cancer.

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Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9675450 ◽

2019 ◽

Vol 2019 ◽

pp. 1-26

Author(s):

Liubing Hu ◽

Yan Wang ◽

Zui Chen ◽

Liangshun Fu ◽

Sheng Wang ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Hela Cells ◽

Cell Apoptosis ◽

Hsp90 Inhibitor ◽

Cervical Cancer Cells ◽

Ros Scavenger ◽

Induced Apoptosis ◽

Human Cervical Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.

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Herpes virus specified early proteins induce cellular DNA synthesis in virus infected cervical cancer cells

European Journal of Cancer and Clinical Oncology ◽

10.1016/0277-5379(87)90620-1 ◽

1987 ◽

Vol 23 (11) ◽

pp. 1771

Author(s):

P. Kulaaa ◽

M. Lehtinen ◽

O.-P. Kallioniemi ◽

J. Paavonen

Keyword(s):

Cervical Cancer ◽

Dna Synthesis ◽

Cancer Cells ◽

Herpes Virus ◽

Early Proteins ◽

Cervical Cancer Cells ◽

Herpès Virus ◽

Cellular Dna

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Downregulation of hsa_circRNA_0001400 Helps to Promote Cell Apoptosis Through Disruption of the circRNA_0001400–miR-326 Sponge in Cervical Cancer Cells

Frontiers in Genetics ◽

10.3389/fgene.2021.779195 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yantao Cai ◽

Chuyu Li ◽

Fang Peng ◽

Shuanghong Yin ◽

Huiyi Liang ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Circular Rnas ◽

Antitumor Effects ◽

Cervical Cancer Cells ◽

Cancer Tissues

Background: In recent years, circular RNAs (circRNAs) have been reported to serve as essential regulators in several human cancers. Nevertheless, the function and mechanism of circRNAs in cervical cancer remain elusive.Methods: Flow cytometry assays were performed to measure cell apoptosis and cell cycle. Colony Formation and transwell chamber were performed to measure cell migration and invasion. Double luciferase reporter for gene analysis was used to detect the interaction between hsa-circRNA_0001400, miR-326, and Akt. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. Tumor Xenograft Modeling was used to evaluate the effect of hsa_circRNA_0001400_siRNA in vivo.Results: In the present study, we showed that hsa_circRNA_0001400 was highly expressed in cervical cancer tissues relative to in matched normal tissue. We found that hsa_circRNA_0001400_siRNA significantly promoted the apoptosis of cervical cancer cells and arrested the cell cycle and migration of cervical cancer cells. We showed that hsa_circRNA_0001400_siRNA can inhibit the protein expression of Akt and that the inhibition of miR-326 could rescue the inhibition of Akt in cervical cancer cells. We found that has-miR-326 was downregulated in cervical cancer tissues and hsa_circRNA_0001400_siRNA could increase the gene expression of has-miR-326. We also observed that hsa_circRNA_0001400_siRNA inhibited the growth and angiogenesis of SiHa xenografts in nude mice.Conclusion: In conclusion, this study provides evidence that the hsa_circRNA_0001400–miR-326–Akt network promotes cervical cancer progression. Notably, our findings demonstrate the novel antitumor effects of hsa_circRNA_0001400_siRNA in cervical cancer.

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Anti-Cancer Effects of miR-181/PTEN/PI3K/Akt Signaling Pathway Suppressed Cell Proliferation and Migration of Human Cervical Cancer

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2311 ◽

2020 ◽

Vol 10 (5) ◽

pp. 615-623

Author(s):

Xiuling Wang ◽

Lan Luo ◽

Lina Xu ◽

Yumin Chen ◽

Xiaofei Liu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cell Apoptosis ◽

Antitumor Effect ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Protein Levels ◽

Ldh Activity ◽

Cervical Cancer Cells

Cervical cancer ranks the second in the incidence of common women malignant tumors, which is the commonest malignant tumor in women's reproductive organs. In present research, we evaluated the possible antitumor effect of miR-181 on cervical cancer and explored the molecular mechanism of this phenomenon. Briefly, MTT, LDH activity kit and flow cytometry were used to detect cell growth, LDH activity and cell apoptosis rate of HeLa cells. The experiment correlation protein expression levels of PTEN, phosphatidylinositol-3-hydroxykinase (PI3K) and phosphorylation (p)-Akt (protein kinase B) were measured by Western blot analysis. In present research, this research observed that miR-181 weakened the cell proliferation activity of cervical cancer cells and induced their caspase3/9 to promotion of cell apoptosis. PTEN expression was induced at the genetic and protein levels, and the PI3K/Akt expressions were inhibited at the protein levels in cervical cancer cells. SiPTEN weakened the antitumor effect of miR-181 on cervical cancer by activation of PI3K/Akt signaling pathway.

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STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells

Oncotarget ◽

10.18632/oncotarget.17641 ◽

2017 ◽

Vol 8 (28) ◽

pp. 46249-46261 ◽

Cited By ~ 10

Author(s):

Xi Pan ◽

Binyuan Jiang ◽

Jianhao Liu ◽

Juan Ding ◽

Yuehui Li ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Cervical Cancer Cells

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miR-21 Inhibits Cell Proliferation and Apoptosis Through Regulating the Phosphatase and Tensin Homolog/Phosphoinositide 3-Kinase/Akt Signaling Pathway in Cervical Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2244 ◽

2020 ◽

Vol 10 (2) ◽

pp. 276-280

Author(s):

Zhijia Zhan ◽

Xiaoyan Xu ◽

Zining Li ◽

Xiujuan Chen ◽

Qian Li ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Laser Scanning ◽

Annexin V ◽

Akt Signaling ◽

Laser Scanning Microscopy ◽

Confocal Laser ◽

Cervical Cancer Cells

A variety of miRNAs regulate cellular physiology and tumor cells. miR-21 regulates tumorigenesis though the modulating cell apoptosis, migration and invasiveness via activating PTEN/PI3K signaling pathway. This study aimed to assess miR-21’s effect on cervical cancer cells and the underlying mechanisms. HeLa were cultured in DMEM medium. Western blotting was to measure bcl-2, bax, p-Akt, PTEN protein level. Annexin V-FITC was measured to analyze the samples by using confocal laser scanning microscopy. Our result showed that miR-21 significantly induced the cell apoptosis of HeLa via decreasing the protein expression of bcl-2. miR-21 markedly inhibited PI3K/Akt signaling, increased PTEN level, induced cancer cell apoptosis and retarded the tumor angiogenesis and proliferation. miR-21 could regulate the proliferation of HeLa via upregulation of PTEN and downregulation of PI3K/Akt pathway, which provides a novel therapeutic insight for the therapy of cervical cancer.

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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

Cancers ◽

10.3390/cancers13184612 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4612

Author(s):

Ya-Hui Chen ◽

Jyun-Xue Wu ◽

Shun-Fa Yang ◽

Mei-Ling Chen ◽

Tze-Ho Chen ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Phase Cell ◽

Anticancer Effect ◽

Cervical Cancer Cells ◽

Human Cervical Cancer Cells ◽

Human Cervical Cancer

Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.

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Knockdown of RNF6 Inhibits Cervical Cancer HeLa Cells Growth by Suppressing the MAPK/ERK Signaling

10.21203/rs.3.rs-69894/v1 ◽

2020 ◽

Author(s):

Kang Zhu ◽

He Bai ◽

Mingzhu Mu ◽

Yuanyuan Xue ◽

Zhao Duan

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Hela Cells ◽

Cell Apoptosis ◽

Biological Significance ◽

Ring Finger ◽

Interactive Analysis ◽

Cervical Cancer Cells

Abstract Background Given its crucial role in human malignancies, how Ring finger protein 6 (RNF6) functions in cervical cancer has yet to be elucidated. In our research, we explored the biological significance of RNF6 in cervical cancer HeLa cells and its possible regulatory mechanism. Methods The expression levels of RNF6 mRNA and protein in cervical cancer tissues and cells were both analyzed, the former by Gene Expression Profiling Interactive Analysis (GEPIA), and the latter by quantitative real-time PCR (qRT-PCR) and immunohistochemistry assays. In vitro cell proliferation was tested through MTT assay and flow cytometer was used to detected Cell apoptosis. The activation of ERK(extracellular signal regulated kinase) was explored by Western Blot. Results In the present research, we found that the expression of RNF6 was high in both primary tissues and cervical cancer cells. RNF6 could promote cervical cancer HeLa cells growth. Once knockdown of RNF6 in cervical cancer cells, cell proliferation could be suppressed and cell apoptosis was promoted. Moreover, its elevation had an adverse effect on the prognosis of cervical cancer. Further studies showed that ERK activation is one of the potential mechanisms. Conclusion These findings provided evidence that the up-regulated RNF6 could activate the MAPK/ERK pathway to regulate the cell growth in cervical cancer, which suggested that RNF6 could be a promising target for diagnosis and treatment for cervical cancer.

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