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. 2015 May 1;8(5):4923-32.
eCollection 2015.

LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells

Yuxiu Gao  1 , Ning Shan  2 , Cheng Zhao  1 , Yunhai Wang  1 , Fuliang Xu  1 , Jiacun Li  3 , Xiaoqian Yu  3 , Lifeng Gao  3 , Zhengjun Yi  1
Affiliations

LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells

Yuxiu Gao et al. Int J Clin Exp Pathol. .

Abstract

Background and objective: Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin.

Methods: SKOV3, OV-90 and SKOV3(DDP) cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models.

Results: LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models.

Conclusions: Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients.

Keywords: LY2109761; Ovarian cancer; chemotherapy; transforming growth factor-beta.

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Figures

Figure 1
Figure 1
Effect of LY2109761 on p-SMAD2. A, RT-PCR assay; B, Western blot assay.
Figure 2
Figure 2
Effects of LY2109761 on cell growth and apoptosis. SKOV3 and OV-90 cells were treated with 0.5, 5 and 10 uM of LY2109761 for 1-3 days. The growth inhibitory effects of LY2109761 on cells by MTT assay (A, B). The apoptosis effects of LY2109761on cells by ELISA assay (C, D). Vs control; *P < 0.05, **P < 0.01.
Figure 3
Figure 3
Combination of LY2109761 with DDP efficiently reduces the viability and increases the apoptosis of OC cells. SKOV3 and OV-90 cells were treated with 0.5, 5 and 10 uM of LY2109761 in combination with DDP for 72 h then cell viability was determined by MTT assay and ELISA assay as described in Materials and Methods. Data are expressed as mean ± SD. Student’s t-test was applied for statistical analysis for comparison between DDP treatment and combined treatment. *P < 0.05; **P < 0.01.
Figure 4
Figure 4
Combination of LY2109761 with DDP on tumorigenicity in nude mice. SKOV3 and SKOV3DDP cells were injected into nude mice, as described in Materials and methods. Tumor volume was determined every 4 days for 28 days. At the end of the experiment, animals were sacrificed and tumors were excised for volume measurement and histological study. A. Growth curve of tumor xenografts in SKOV3 cells; B. Growth curve of tumor xenografts in SKOV3DDP cells; *P < 0.05, **P < 0.01 ,compared to the controls. C. The resected tumors were stained with antibodies against p-SMAD2 Representative images of the staining are shown. D. The resected tumors were stained with antibodies against Ki-67.The percentages of Ki-67-positive cells were indicated. *P < 0.05. E. The resected tumors were stained with TUNEL. The percentages of TUNEL-positive cells were indicated. *P < 0.05.
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References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA. 2012;62:10–29. - PubMed
    1. Sudo T. Molecular-targeted therapies for ovarian cancer: prospects for the future. Int J Clin Oncol. 2012;17:424–429. - PubMed
    1. Sueblinvong T, Ghebre R, Iizuka Y, Pambuccian SE, Isaksson Vogel R, Skubitz AP, Bazzaro M. Establishment, characterization and downstream application of primary ovarian cancer cells derived from solid tumors. PLOS One. 2012;7:e50519. - PMC - PubMed
    1. McKeage MJ. New-generation platinum drugs in the treatment of cisplatin-resistant cancers. Expert Opin Investig Drugs. 2005;14:1033–46. - PubMed
    1. Tewari K, Mehta R, Burger R, et al. Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs. 2005;10:413–42. - PubMed

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