-
Hongwei Tian, Shengyong Liu,
Junfeng Zhang,
Shuang Zhang,
Lin Cheng,
Can Li,
Xiaomei Zhang,
Lixia Dail,
Ping Fan,
Lei Dai,
Nv Yan,
Ruibo Wang,
Yuquan Wei,
Hongxin Deng
[show abstract]
[hide abstract]
ABSTRACT: Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is abundantly expressed in a variety of cancer cells, including lung cancer cells, resulting in low sensitivity of these cells to various apoptotic stimuli; Cisplatin (CDDP), a commonly used chemotherapeutic agent of several cancers, has a major limitation because of its toxicity at high concentration. In the present study, we constructed a plasmid encoding Survivin shRNA to knockdown survivin with low dose DDP both in vitro and in vivo. The specificity and potency of the shRNA were validated by western blot, flow cytometric and MTT in H292 lung cancers cells. In vivo, therapy experiments were conducted on nude mice bearing H292 xenograft tumors. The Survivin shRNA expression plasmid was administered systemically in combination with low-dose CDDP on a frequent basis. Assessments of angiogenesis, cell proliferation and apoptosis were performed by using immunohistochemistry against CD31, Ki67 and TUNEL assays, respectively. The results revealed that treatment with the Survivin shRNA plus low-dose CDDP reduced volume by approximately 83.13% compared with the blank control (P < 0.01), accompanied with angiogenesis inhibition (p < 0.01), tumor cell proliferation suppression (p < 0.05) and apoptosis induction (p < 0.01). Moreover, combination treatment also significantly reduced the mean tumor volume compared with other treatment alone (p < 0.05). Taken together, our study suggested that silencing of survivin sensitized H292 lung cancer cells to chemotherapy of CDDP, suggesting potential applications of the combined approach in the treatment of lung cancer.
Journal of Biomedical Nanotechnology 08/2012; 8(4):633-41. · 4.22 Impact Factor
-
Na Zhang,
Yang Yang,
Lin Cheng,
Xiao-mei Zhang,
Shuang Zhang,
Wei Wang, Sheng-yong Liu,
Shu-ya Wang,
Rui-bo Wang,
Wen-jing Xu,
Lei Dai,
Nv Yan,
Ping Fan,
Li-xia Dai,
Hong-wei Tian,
Lei Liu,
Hong-xin Deng
[show abstract]
[hide abstract]
ABSTRACT: It has been shown that Caspy2, a zebrafish active caspase, can efficiently suppress the growth of malignant tumor. The present study was designed to test whether combined gene therapy with IP-10, a potent antitumor chemokine, and Caspy2 would improve therapy efficacy. Recombinant plasmid expressing both Caspy2 and IP-10 genes was mixed with DOTAP-cholesterol nanoparticles. Immunocompetent mice bearing CT26 colon carcinoma, B16-F10 melanoma, and 4T1 breast carcinoma were treated with the complex. We found that the combined gene therapy more efficiently inhibited tumor growth, while efficiently prolonging the survival of tumor-bearing animals, compared with monotherapy. Moreover, a significant reduction in spontaneous lung metastasis could be observed in the 4T1 breast carcinoma model. Infiltration of CD8(+) T lymphocytes was also observed. In addition, apoptotic cells were widely detected by TUNEL assay and caspase-3 immunostaining in coadministered tumor tissues. The combination treatment also successfully inhibited angiogenesis and tumor cell proliferation as assessed by CD31 and Ki-67 immunostaining, respectively. Furthermore, depletion of CD8(+) T lymphocytes could significantly abrogate the antitumor activity, whereas the depletion of CD4(+) cells or natural killer cells showed partial abrogation. Rechallenged CT26 tumors were rejected in all of the surviving mice treated by combination therapy. Our results suggest that combined therapy with Caspy2 and IP-10 can significantly enhance antitumor activity by acting as an immune response initiator, apoptosis inducer, and angiogenesis inhibitor, which may be important for further applications in clinical cancer therapy.
Human gene therapy 05/2012; 23(8):837-46. · 4.20 Impact Factor
-
Shuang Zhang,
Zhixing Cao,
Hongwei Tian,
Guobo Shen,
Yongping Ma,
Huanzhang Xie,
Yalin Liu,
Chengjian Zhao,
Senyi Deng,
Yang Yang, [......],
Wei Wang,
Lixia Dai,
Shuai Shi,
Lin Cheng,
Youli Pan,
Shan Feng,
Xia Zhao,
Hongxin Deng,
Shengyong Yang,
Yuquan Wei
[show abstract]
[hide abstract]
ABSTRACT: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.
In this investigation, we adopted a restricted de novo design method to design VEGFR2 inhibitors. We selected the most potent compound SKLB1002 and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro. Tumor xenografts in zebrafish and athymic mice were used to examine the in vivo activity of SKLB1002.
The use of the restricted de novo design method indeed led to a new potent VEGFR2 inhibitor, SKLB1002, which could significantly inhibit HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis was conducted, which indicated that SKLB1002 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal-regulated kinase, focal adhesion kinase, and Src. In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/d SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay.
Our findings suggest that SKLB1002 inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.
Clinical Cancer Research 05/2011; 17(13):4439-50. · 7.74 Impact Factor
-
Shuang Zhang,
Hongwei Tian,
Qingyuan Jiang,
Li Li,
Yu Ding,
Lei Dai,
Yu Xiang,
Guobo Shen,
Lin Cheng,
Qiaorong Huang, [......],
Xiaomei Zhang,
Yongping Ma,
Na Zhang, Shengyong Liu,
Wei Wang,
Lixia Dai,
Yiming Li,
Xia Zhao,
Yuquan Wei,
Hongxin Deng
[show abstract]
[hide abstract]
ABSTRACT: In the present study, we have used plasmid-based RNA interference (RNAi) strategy to downregulate the expression of epidermal growth factor receptor (EGFR) in EGFR wild-type (H292) and mutant (H1975) lung tumor models. The targeted knockdown of EGFR by small hairpin RNA not only inhibited growth of H292 xenograft but also inhibited H1975 lung cancer cell and xenograft, which bore L858R/T790M EGFR and was resistant to EGFR tyrosine kinase inhibitors. These data demonstrated that small hairpin RNA was an effective therapy against mutant EGFR-expressing cancer cells and thus considered to be a promising strategy in the treatment of lung cancers.
Cancer Investigation 01/2011; 29(10):701-8. · 1.85 Impact Factor
