Experimental Study of AntiBreast Cancer Cells with Tamoxifen Combined with Antisense Oligonucleotide Targeting Survivin mRNA_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SONG Wenzhe ¹ , SONG Yan ² , TAN Yan ³ , FANG Yanqiu ³

1.Department of General Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China;;
2.Department of General Surgery, ChinaJapan Union Hospital, Jilin University, Changchun 130033, China;;
3.Department of Central Laboratory, The First Hospital, Jilin University, Changchun 130021, China;

Corresponding author：

Keywords：

Breast cancer; Tamoxifen; Survivin; Antisense oligonucleotide; Caspase-3

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Objective To study the effects on MCF-7 breast cancer cells with combination of tamoxifen（TAM） and antisense oligonucleotide （ASODN） targeting survivin mRNA.
Methods MCF-7 breast cancer cells were treated with a 20 mer ASODN targeting survivin mRNA and TAM, which were divided into three groups: TAM group (treated by TAM only), ASODN group (by ASODN only), and TAM+ASODN combined group (by TAM+ASODN combination). The growth inhibition of MCF-7 cells, the changes of cell cycles and apoptotic rate, the positive rate of survivin mRNA expression, and the activity of caspase-3 were tested by MTT, flow cytometry, hybridization in situ, and spectrophotometric method, respectively.
Results The rate of growth inhibition of MCF-7 cells in the TAM+ASODN combined group was (62.26±3.92)%, which was significantly higher than that in the TAM group 〔(42.30±6.63)%〕 or ASODN group 〔(54.77±9.99)%〕, P lt;0.05. The apoptotic rate of MCF-7 cells was (28.08±4.32)% in the TAM+ASODN combined group, which was significantly higher than that in the TAM group 〔(18.94±4.01)%〕 or ASODN group 〔(21.12±3.95)%〕, P lt;0.01. The effect of arresting MCF-7 cells in G0/G1 phase in the TAM+ASODN combined group was ber than that in the TAM or ASODN group (P lt;0.05, P lt;0.01). The positive rate of survivin mRNA in the TAM+ASODN combined group was (13.38±3.45)%, which was significantly lower than that in the TAM group 〔(39.67±7.42)%〕 or ASODN group 〔(27.50±5.80)%〕, P lt;0.01. The activity of caspase-3 in the TAM+ASODN combined group （0.93±0.13） was significantly higher than that in the TAM group (0.50±0.09) or ASODN group (0.64±0.08), P lt;0.01.
Conclusion The ASODN targeting survivin mRNA can promote the apoptosis of MCF-7 breast cancer cells, and make MCF-7 cells more sensitive to tamoxifen.

Citation： SONG Wenzhe ,SONG Yan,TAN Yan,FANG Yanqiu. Experimental Study of AntiBreast Cancer Cells with Tamoxifen Combined with Antisense Oligonucleotide Targeting Survivin mRNA. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(9): 922-926. doi: Copy

1.	Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma [J]. Nat Med, 1997; 3(8): 917921.
2.	谢贻祥, 孟刚. survivin在乳腺癌中的表达及其意义 [J]. 中国普外基础与临床杂志, 2007; 14(3): 263264.
3.	Ansell SM, Arendt BK, Grote DM, et al. Inhibition of survivin expression suppresses the growth of aggressive nonHodgkin’s lymphoma [J]. Leukemia, 2004; 18(3): 616623.
4.	冯立民, 姜希宏, 乌新林, 等. survivin反义寡核苷酸（ASODN）诱导胆囊癌细胞凋亡的研究 [J]. 中国普外基础与临床杂志, 2006; 13(3): 298301.
5.	陈曦海, 张岂凡, 马荣. 反义survivin诱导胃癌SGC7901细胞凋亡及逆转耐药的研究 [J]. 中国普外基础与临床杂志, 2007; 14(1): 6367.
6.	Song X, Wang JB, Yin DL, et al. Downregulation of lung resistance related protein by RNA interference targeting survivin induces the reversal of chemoresistances in hepatocellular carcinoma [J]. Chin Med J (Engl), 2009; 122(21): 26362642.
7.	Zaffaroni N, Pennati M, Collella G, et al. Expression of the antiapoptotic gene survivin correlates with taxol resistance in human ovarian cancer [J]. Cell Mol Life Sci, 2002; 59(8): 14061412.
8.	Olie RA, SimesWüst AP, Baumann B, et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy [J]. Cancer Res, 2000; 60(11): 28052809.
9.	Ryan BM, O’Donovan N, Duffy MJ. Survivin: a new target for anticancer therapy [J]. Cancer Treat Rev, 2009; 35(7): 553562.
10.	Dai DJ, Lu CD, Lai RY, et al. Survivin antisense compound inhibits proliferation and promotes apoptosis in liver cancer cells [J]. World J Gastroenterol, 2005; 11(2): 193199.
11.	孙艳, 李勇, 范立侨, 等. survivin反义寡核苷酸对人卵巢癌细胞株中survivin和SMAC/DIABLO基因表达的影响 [J]. 南方医科大学学报, 2007; 27(10): 15711574.
12.	Mita AC, Mita MM, Nawrocki ST, et al. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics [J]. Clin Cancer Res, 2008; 14(16): 50005005.
13.	Yamamoto H, Ngan CY, Monden M. Cancer cells survive with survivin [J]. Cancer Sci, 2008; 99(9): 17091714.
14.	Bendardaf R, Ristamaki R, Syrjanen K, et al. Bcl2 expression significantly correlates with thymidylate synthase expression in colorectal cancer patients [J]. World J Gastroenterol, 2008; 14(40): 62186223.
15.	Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl2 family [J]. J Cell Sci, 2009; 122(Pt 4): 437441.
16.	Kang MH, Reynolds CP. Bcl2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy [J]. Clin Cancer Res, 2009; 15(4): 11261132.
17.	Spender LC, Inman GJ. Targeting the BCL2 family in malignancies of germinal centre origin [J]. Expert Opin Ther Targets, 2009; 13(12): 14591472.
18.	Patel MP, Masood A, Patel PS, et al. Targeting the Bcl2 [J]. Curr Opin Oncol, 2009; 21(6): 516523.
19.	Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin [J]. Nature, 1998; 396(6711): 580584.
20.	Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16IN K4a and Cdk2/cyclin E complex activation [J]. Oncogene, 2000; 19(29): 32253234.
21.	戴德坚, 吴丹, 孟化, 等. 反义survivin脂质体复合物对肝癌细胞生长凋亡和细胞周期的影响 [J]. 中华肿瘤杂志, 2005; 27(10): 581585.
22.	Pradelli LA, Bénéteau M, Ricci JE. Mitochondrial control of caspasedependent and independent cell death [J]. Cell Mol Life Sci, 2010; 67(10): 15891597.
23.	Tamm I, Wang Y, Sausville E, et al. IAPfamily protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs [J]. Cancer Res, 1998; 58(23): 53155320.
24.	Li YH, Wang C, Meng K, et al. Influence of survivin and caspase3 on cell apoptosis and prognosis in gastric carcinoma [J]. World J Gastroenterol, 2004; 10(13): 19841988.
25.	Wang JX, Zheng S. Caspase3 and survivin expression in pediatric neuroblastoma and their roles in apoptosis [J]. Chin Med J (Engl), 2004; 117(12): 18211824.

1. Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma [J]. Nat Med, 1997; 3(8): 917921.
2. 谢贻祥, 孟刚. survivin在乳腺癌中的表达及其意义 [J]. 中国普外基础与临床杂志, 2007; 14(3): 263264.
3. Ansell SM, Arendt BK, Grote DM, et al. Inhibition of survivin expression suppresses the growth of aggressive nonHodgkin’s lymphoma [J]. Leukemia, 2004; 18(3): 616623.
4. 冯立民, 姜希宏, 乌新林, 等. survivin反义寡核苷酸（ASODN）诱导胆囊癌细胞凋亡的研究 [J]. 中国普外基础与临床杂志, 2006; 13(3): 298301.
5. 陈曦海, 张岂凡, 马荣. 反义survivin诱导胃癌SGC7901细胞凋亡及逆转耐药的研究 [J]. 中国普外基础与临床杂志, 2007; 14(1): 6367.
6. Song X, Wang JB, Yin DL, et al. Downregulation of lung resistance related protein by RNA interference targeting survivin induces the reversal of chemoresistances in hepatocellular carcinoma [J]. Chin Med J (Engl), 2009; 122(21): 26362642.
7. Zaffaroni N, Pennati M, Collella G, et al. Expression of the antiapoptotic gene survivin correlates with taxol resistance in human ovarian cancer [J]. Cell Mol Life Sci, 2002; 59(8): 14061412.
8. Olie RA, SimesWüst AP, Baumann B, et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy [J]. Cancer Res, 2000; 60(11): 28052809.
9. Ryan BM, O’Donovan N, Duffy MJ. Survivin: a new target for anticancer therapy [J]. Cancer Treat Rev, 2009; 35(7): 553562.
10. Dai DJ, Lu CD, Lai RY, et al. Survivin antisense compound inhibits proliferation and promotes apoptosis in liver cancer cells [J]. World J Gastroenterol, 2005; 11(2): 193199.
11. 孙艳, 李勇, 范立侨, 等. survivin反义寡核苷酸对人卵巢癌细胞株中survivin和SMAC/DIABLO基因表达的影响 [J]. 南方医科大学学报, 2007; 27(10): 15711574.
12. Mita AC, Mita MM, Nawrocki ST, et al. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics [J]. Clin Cancer Res, 2008; 14(16): 50005005.
13. Yamamoto H, Ngan CY, Monden M. Cancer cells survive with survivin [J]. Cancer Sci, 2008; 99(9): 17091714.
14. Bendardaf R, Ristamaki R, Syrjanen K, et al. Bcl2 expression significantly correlates with thymidylate synthase expression in colorectal cancer patients [J]. World J Gastroenterol, 2008; 14(40): 62186223.
15. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl2 family [J]. J Cell Sci, 2009; 122(Pt 4): 437441.
16. Kang MH, Reynolds CP. Bcl2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy [J]. Clin Cancer Res, 2009; 15(4): 11261132.
17. Spender LC, Inman GJ. Targeting the BCL2 family in malignancies of germinal centre origin [J]. Expert Opin Ther Targets, 2009; 13(12): 14591472.
18. Patel MP, Masood A, Patel PS, et al. Targeting the Bcl2 [J]. Curr Opin Oncol, 2009; 21(6): 516523.
19. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by survivin [J]. Nature, 1998; 396(6711): 580584.
20. Suzuki A, Hayashida M, Ito T, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16IN K4a and Cdk2/cyclin E complex activation [J]. Oncogene, 2000; 19(29): 32253234.
21. 戴德坚, 吴丹, 孟化, 等. 反义survivin脂质体复合物对肝癌细胞生长凋亡和细胞周期的影响 [J]. 中华肿瘤杂志, 2005; 27(10): 581585.
22. Pradelli LA, Bénéteau M, Ricci JE. Mitochondrial control of caspasedependent and independent cell death [J]. Cell Mol Life Sci, 2010; 67(10): 15891597.
23. Tamm I, Wang Y, Sausville E, et al. IAPfamily protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs [J]. Cancer Res, 1998; 58(23): 53155320.
24. Li YH, Wang C, Meng K, et al. Influence of survivin and caspase3 on cell apoptosis and prognosis in gastric carcinoma [J]. World J Gastroenterol, 2004; 10(13): 19841988.
25. Wang JX, Zheng S. Caspase3 and survivin expression in pediatric neuroblastoma and their roles in apoptosis [J]. Chin Med J (Engl), 2004; 117(12): 18211824.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Experimental Study of AntiBreast Cancer Cells with Tamoxifen Combined with Antisense Oligonucleotide Targeting Survivin mRNA

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