Chemically modified siRNA directed against the KDR gene inhibits the proliferation of breast cancer cells

Zhang, Jinyu; Zhang, Xiao; Hou, Lin; Li, Quan; Xue, Meilan

doi:10.3892/mmr_00000072

Cited by 4 publications

(5 citation statements)

References 19 publications

(21 reference statements)

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“…In accordance with our previous results showing that KDR-siRNA markedly decreased KDR gene expression and suppressed tumor growth in the xenograft model [13], using the siRNA-targeting KDR gene, we were able to silence the expression of KDR at the protein and mRNA levels. However, the molecular mechanisms underlying the anti-cancer effects of KDR-siRNA are not clearly understood.…”

Section: Discussionsupporting

confidence: 77%

“…It provides us with an effective and simple method to specifically downregulate target genes [12]. We previously showed that KDR-siRNA suppressed tumor growth in a xenograft model [13], suggesting that KDR-siRNA might be an effective approach for the treatment of breast cancer. Apoptosis, also known as programmed cell death, is involved in the normal development of multicellular organisms and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of KDR expression induces apoptosis in breast cancer cells

Zhang

Yan

et al. 2014

Cellular and Molecular Biology Letters

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Angiogenesis plays a crucial role in the growth, invasion and metastasis of breast cancer. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are the key regulators of tumor angiogenesis. VEGFR-2, known as the kinase insert domain receptor (KDR), is a key receptor involved in malignant angiogenesis. We previously showed that knocking down KDR with short interference RNA (KDR-siRNA) markedly decreased KDR expression and suppressed tumor growth in a xenograft model. However, the mechanisms underlying the anti-cancer effects of KDR-siRNA are not clearly understood. This study aimed to elucidate the molecular mechanisms that induce apoptosis in human breast cancer MCF-7 cells after transfection with KDRsiRNA. We studied the effects of KDR-siRNA on proliferation, apoptosis, antiapoptotic and pro-apoptotic proteins, mitochondrial membrane permeability, cytochrome c release and caspase-3 activity. The results indicated that KDRsiRNA treatment significantly inhibited the proliferation and induced the apoptosis of MCF-7 cells, reduced the levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xl, and increased the level of the pro-apoptotic protein Bax, resulting in a decreased Bcl-2/Bax ratio. KDR-siRNA also enhanced the mitochondrial membrane permeability, induced cytochrome c release from the mitochondria, upregulated apoptotic protease-activating factor-1 (Apaf-1), cleaved caspase-3, and increased caspase-3 activity in MCF-7 cells. Furthermore, KDR-siRNA-induced apoptosis in MCF-7 cells was blocked by the caspase inhibitor Z-VAD-FMK, suggesting a role of caspase activation in the induction of apoptosis. These results indicate that the Bcl-2 family proteins and caspase-related mitochondrial pathways are primarily involved in KDR-siRNAinduced apoptosis in MCF-7 cells and that KDR might be a potential therapeutic target for human breast cancer treatments.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Downregulation of KDR expression induces apoptosis in breast cancer cells

Zhang

Yan

et al. 2014

Cellular and Molecular Biology Letters

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“…VEGF/VEGFR-2 signaling system enhances ovarian cancer cell proliferation and survival [10][11][12]. Moreover, experiments on cancer cell lines proved that suppression of VEGFR-2 expression with siRNA inhibits proliferation of human breast cancer cells, and suppresses tumor growth in mice xenograft model [18]. Furthermore, recent studies showed that therapies with anti-VEGF antibody bevacizumab [19] or oral tyrosine kinase inhibitors targeting receptors for pro-angiogenic growth factors, including VEGFR-2 [20][21][22], reduce tumor growth, angiogenesis, ascites production, and improve survival in murine models of EOC.…”

Section: Variablementioning

confidence: 98%

Cyclin I correlates with VEGFR-2 and cell proliferation in human epithelial ovarian cancer

Cybulski

Jarosz

Nowakowski

et al. 2012

Gynecologic Oncology

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“…The KDR gene is specifically expressed in certain tumor and vascular endothelial cells; therefore the KDR promoter has been used to express target genes in certain tumors due to its tumor-specific expression (20)(21)(22). In the present study, we report a potential treatment modality for breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated tissue-targeted expression of the CDglyTk gene for the treatment of breast cancer

Su¹,

Su²,

Huang³

2012

Molecular Medicine Reports

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The aim of this study was to evaluate the selective killing efficacy of adenovirus (Ad)-mediated double suicide genes driven by the kinase domain-containing receptor (KDR) promoter in human breast cancer cells and vascular endothelial cells. Two Ad-mediated double suicide gene systems [with the two suicide genes, thymidine kinase (TK) and cytosine deaminase (CD)] with the KDR promoter (Ad-KDRP-CDglyTK) and the cytomegalovirus (CMV) promoter (Ad-CMV-CDglyTK) were established and transfected into the KDR-expressing MCF7 human breast cancer, EC304 human vascular endothelial and LS174T human colon carcinoma, which does not express KDR, cell lines. The selective killing efficiency and specificity of the double suicide gene system were measured in vitro by the analysis of cellular proliferation and assayed in vivo by subcutaneous injection of MCF7 cells into nude mice. The microvessel density (MVD) in the transplanted tumor was determined by immunohistochemical staining of CD34 cells. Our results showed that the transgenic CDglyTK genes were expressed in three cell lines (MCF7, ECV304 and LS174T) infected with Ad-CMV-CDglyTK. However, of the cells infected with Ad-KDRP-CDglyTK, the transgenic CDglyTK gene was only expressed in the KDR-expressing MCF7 and ECV304 cells, but not in the KDR-deficient LS174T cells. Cell proliferation was significantly reduced in a dose-dependent manner by pre-treatment with ganciclovir (GCV) and 5-fluorocytosine (5-FC) in MCF7 and ECV304 cells with transfected KDRP-CDglyTK genes and the three cell lines transfected with the CMV-CDglyTK genes. Similar results were not observed in the LS174T cells with transfected KDRP-CDglyTK genes. The results of this study show that the tumor-targeted expression of CDglyTK driven by the KDR promoter has a high specificity and performance. The killing effect of the CD/TK fusion gene in the target cells was significantly increased compared with the single suicide gene. The cell cycle of MCF7 and ECV304 cells transfected with KDRP-CDglyTK genes was arrested at the S phase following treatment with the prodrugs. The tumors formed by the MCF7 cells with the double suicide gene system were much smaller and the MVD of the tumor tissue was significantly decreased compared with the control. This study demonstrates that tumor‑targeted expression of the CDglyTK gene driven by the KDR promotor may be a novel strategy for the gene therapy of human breast cancer.

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Chemically modified siRNA directed against the KDR gene inhibits the proliferation of breast cancer cells

Cited by 4 publications

References 19 publications

Downregulation of KDR expression induces apoptosis in breast cancer cells

Downregulation of KDR expression induces apoptosis in breast cancer cells

Cyclin I correlates with VEGFR-2 and cell proliferation in human epithelial ovarian cancer

Adenovirus-mediated tissue-targeted expression of the CDglyTk gene for the treatment of breast cancer

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