Basic Research of the Adenovirus-mediated hCTR1 Transfection on the Treatment of Cisplatin Resistant Cervical Cancer

WU Xiu-li, GUO Tao, CAI Hua-wei

Abstract

To induce cisplatin-resistant cervical squamous carcinoma cell line and investigate the drug resistant mechanisms and adenovirus trans-gene therapeutical treatment. Methods The cisplatin-resistant subline, designated C-33A/cis, was originated by growing parental C-33A cells with gradually increasing doses of cisplatin. The cytotoxicity of cisplatin was determined by CCK-8 assay, and the CTR1 expression was measured by Western blot. Subcutaneous xenograft cervical tumor model was established by cisplatin-resistant C-33A/cis cell line. Recombinant adenovirus ad-hCTRl was transfected into tumor by intratumoral injection and combined with cisplatin chemotherapy. The changes in the volume of tumor were observed and the mice were executed at 10,h day after the last injection, and the expression of CTR1 in tumor tissues was detected by immunohistochemistry. Results Cisplatin-resistant cervical carcinoma ОЗЗА/cis cells were successfully induced by gradually increased concentration of cisplatin. The cytotoxic IC50 value of cisplatin on C-33A/cis had been upgraded from (1.86±0. 08) to (8. 11±0. 21) \xmol/L, while the CTR1 was found decreased by Western blot assay. Immunohistochemical analysis indicated that CTR1 expression was increased by intratumoral injection of adenovirus ad-hCTRl, and the tumor growth of C-33A/cis drug-resistant cervical carcinoma xenograft was inhibited by ad-hCTRl transfection combined with cisplatin. Conclusion The combination therapy of ad-hCTR\ transfection and cisplatin was effective to inhibit the growth of drug-resistant C-33A/cis tumor.

 

Keywords: Cervical cancer, Cisplatin, CTR1, Adenovirus transfection


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LOZANO R, NAGIIAVI M, FOREMAN K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet , 2012, 380 ( 9859 ): 2095-2128.

CHEN W, ZHENG R. ZENG H, et al. Annual report on status of cancer in China, 2011. Chin J Cancer Res,2015,27 (1):2-12.

GO RS, ADJEI A A. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol, 1999,17( 1):409-422.

ROSA DD, MEDEIROS LR, EDELWEISS MI, et al. Adjuvant platinum-based chemotherapy for early stage cervical cancer. Cochrane Database Syst Rev, 2012, 13 ( 6) : CD005342.

ISHIDAS, MCCORMICK F, SMITH-MCCUNE K. et al. Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell, 2010, 17 ( 6 ): 574-583.

WU Z, LIU Q, LIANG X, et al. Reactivity of platinum- based antitumor drugs towards a Met- and His-rich 20 mer peptide corresponding to the N-terminal domain of human copper transporter 1. J Biol Inorg Chem, 2009,14(8): 1313- 1323.

HOLZER AK, VARKI NM, LE QT, et al. Expression of the human copper influx transporter 1 in normal and malignant human tissues. J Histochem Cytochem, 2006» 54 (9):1041-1049.

HOLZER AK, HOWELL SB. The internalization and degradation of human copper transporter 1 following cisplatin exposure. Cancer Res,2006,66(22): 10944-10952.

HOWELL SB, SAFAEI R, LARSON CA, et al. Copper transporters and the cellular pharmacology of the platinum- containing cancer drugs. Mol Pharmacol, 2010, 77 ( 6 ): 887- 894.

LARSON CA, BLAIR BG, SAFAEI R, et al. The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol Pharmacol,2009, 75(2):324-330.

SONG IS. SAVARAJ N, SIDDIK ZH, et al. Role of human copper transporter Ctrl in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther,2004, 3( 12): 1543-1549.

KUO MT, FU S, SAVARAJ N, et al. Role of the human high-af finity copper transporter in copper homeostasis regulation and cisplatin sensitivity in cancer chemotherapy. Cancer Res,2012,72( 18) :4616-4621.

LIANG ZD, STOCKTON D, SAVARAJ N, et al. Mechanistic comparison of human high-af finit у copper transporter 1-mediated transport between copper ion and cisplatin. Mol Pharmacol ,2009,76(4);843-853.


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