Abstract
Objective
To further validate a knockdown approach for circumventing the multidrug resistance gene (MDR1), we used small interfering RNA(siRNA) targeting MDR1 gene to inhibit the expression of MDR1 gene and P-glycoprotein(P-gp) in vivo.
Methods
Ascite tumor xenografts were established by implanting human ovarian carcinoma cells SKOV3/AR intraperitoneally into the nude mice. The mice were randomized into the following three treatment groups with each group six mice respectively: Taxol, Taxol with lipofectamine and Taxol with siRNA/MDR1-lipofectamine intraperitoneal injection. The tumor growth rate and the ascite growth rate of mice were investigated. The expressions of MDR1 gene and P-gp in mice were determined by reverse transcription-polymerase chain reaction(RT-PCR) and immunohistochemistry respctively.
Results
The growth of tumors and ascites in mice treated with Taxol and siRNA/MDR1-lipofectamine was significantly inhibited compared with those in mice of other groups. After 28 days’ treatment, the average tumor weight and ascite volume decreased by 43.6% and 29.7% in the group treated with Taxol and siRNA/MDR1-lipofectamine compared with these treated with Taxol alone (P<0.001). The expressions of MDR1 gene and P-gp in the group treated with Taxol and siRNA/MDR1-lipofectamine were also decreased compared with those in the group treated with Taxol alone (P<0.001).
Conclusion
Small interfering RNA targeting-MDR1 can effectively and specifically suppress the expression of MDR1(P-glycoprotein) and inhibit ovarian cancer growth in vivo.
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References
Roberts PC, Mottillo EP, Baxa AC, et al. Sequential molecular and cellular events during neoplastic Progression:a mouse syngeneic ovarian cancer model[J]. Neoplasia 2005;7: 944–956.
Shabbits JA, Mayer LD. P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anti-cancer drugs [J]. Mol Cancer Ther 2002;1: 205–213.
Hsiao P, Bui T, Ho RJ, et al. In vitro-to-in vivo prediction of P-glycoprotein-based drug interactions at the human and rodent blood-brain barrier[J]. Drug Metab Dispos 2008; 36: 481–484.
Jekerle V, Kassack MU, Reillv RM, et al. Functional comparison of single and doublestranded mdr1 antisense oligodeoxy-nucleotides in human ovarian cancer cell lines[J]. J Pharm Pharmaceut Sci 2005; 8:516–527.
Chen XP, Wang Q, Guan J, et al. Reversing multidrug resistance by RNA interference through the suppression of MDR1 gene in human hepatoma cells[J]. World J Gastroenterol 2006;12:3332–3337.
Zhi S, Liang YJ, Chen ZS, et al. Reversal of MDR1/P-Glycoprotein-mediated multidrug resistance by vector-based RNA interference in vitro and in vivo[J]. Cancer Biol Ther 2006; 5: 39–47.
Pichler A, Zelcer N, Prior J. et al. In vivo RNA interference-mediated ablation of MDR1 P-glycoprotein[J]. Clin Cancer Res 2005; 11: 4487–4494.
Wu H, Hait WN, Yang JM. Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells[J]. Cancer Res 2003; 63: 1515–1519.
Wang R, Dong K, Lin F, et al. Inhibiting proliferation and enhancing chemosensitivity to taxanes in osteosarcoma cells by RNA interference-mediated downregulation of Stathmin expression[J]. Mol Med 2007; 13: 567–575.
Santel A, Aleku M, Keil O, et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy[J]. Gene Ther 2006; 13:1360–1370.
Nie CL, Gao GL, Han J, et al. Human papillomavirus 16 E6, E7 siRNAs inhibit proliferation and induce apoptosis of SiHa cervical cancer cells[J]. Chin J Cancer Res 2008; 20: 301–306.
Minakuchi Y, Takeshita F, Kosaka N, et al. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo[J]. Nucleic Acids Res 2004; 32:e109.
Seibler J, Kleinridders A, Küter-Luks B, et al. Reversible gene knockdown in mice using a tight, inducible shRNA expression system[J]. Nucleic Acids Res 2007; 35: e54.
Duan ZF, Brakora KA, Seiden MV. Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells[J]. Mol Cancer Ther 2004; 3: 833–838.
Piva R, Chiarle R, Manazza AD, et al. Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas[J]. Blood 2006; 107: 689–697.
Czauderna F, Fechtner M, Aygün H, et al. Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA[J]. Nucleic Acids Res 2003; 31: 670–682.
Pulukuri SM, Gondi CS, Lakka SS, et al. RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival and tumorigenicity in vivo[J]. J Biol Chem 2005; 280: 36529–36540.
Xu D, McCarty D, Fernandes A, et al. Delivery of MDR1 small interfering RNA by self-complementary recombinant adeno-associated virus vector[J]. Mol Ther 2005; 11: 523–530.
Xie SM, Fang WY, Liu Z, et al. Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin[J]. J Transl Med 2008; 6:55.
Schiffelers RM, Ansari A, Xu J, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle [J]. Nucleic Acids Res 2004; 32:e149.
Xiao H, Wu Z, Shen H, et al. In vivo reversal of P-glycoprotein-mediated multidrug resistance by efficient delivery of Stealth™ RNAi[J]. Basic Clin Pharmacol Toxicol(in Chinese) 2008;103: 342–348.
Sersa G, Miklavcic D, Cemazar M, et al. Electrochemotherapy in treatment of tumors[J]. Eur J Surg Oncol 2008; 34:232–240.
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This work was supported by the grant from the key project of Jiangxi Bureau of Health Science(No.200506).
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Liu, Fj., Gao, Gl., Tu, Kj. et al. Small interfering RNA targeting MDR1 inhibits ovarian cancer growth and increases efficacy of chemotherapy in vivo . Chin. J. Cancer Res. 21, 318–324 (2009). https://doi.org/10.1007/s11670-009-0318-y
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DOI: https://doi.org/10.1007/s11670-009-0318-y