阻斷胰腺癌平衡型核苷轉運載體對5-氟尿嘧啶誘導細胞凋亡及細胞周期改變的影響_《中國普外基礎與臨床雜志》

作者：

高毅明 , 周予民 , 宋海湖 , 范自平 , 劉浩

上海市第一人民醫院寶山分院普外科(上海 200940);

關鍵詞：

細胞凋亡細胞周期核苷轉運載體 5-氟尿嘧啶潘生丁

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目的研究應用潘生丁(DP)阻斷平衡型核苷轉運載體(hENTs)后，5-氟尿嘧啶(5-FU)對胰腺癌細胞株Panc-1凋亡及細胞周期的影響。方法將Panc-1細胞分為hENTs未阻斷組和hENTs阻斷組，hENTs阻斷組再根據DP濃度分為5 μmol/L DP組和10 μmol/L DP組。各組細胞分別在含有1.5×106 ng/L 5-FU或不含5-FU的培養液中培養24 h后，流式細胞儀檢測細胞的凋亡率和細胞周期改變。結果①各組細胞凋亡檢測結果：在含有1.5×106 ng/L 5-FU培養液中培養24 h后，5 μmol/L 及10 μmol/L DP組的細胞凋亡率明顯高于未阻斷組(P lt;0.05)，10 μmol/L DP組又明顯高于5 μmol/L DP組(P lt;0.05); 在不含5-FU的培養液中培養24 h后，各組之間細胞凋亡率比較差異無統計學意義(P gt;0.05)。②各組細胞周期檢測結果：在含有1.5×106 ng/L 5-FU培養液中培養24 h后，未阻斷組細胞進入合成期(S期)的比例減少，停滯在合成前期(G1期),5 μmol/L DP組及10 μmol/L DP組的細胞進入合成期(S期)的比例較未阻斷組進一步減少(P lt;0.05)，且隨著DP濃度的增加，細胞進入合成期(S期)的比例減少得更多(P lt;0.05)，5 μmol/L DP組和10 μmol/L DP組進入合成期（S期）的比例分別是未阻斷組的87.09%和74.06%。5-FU對細胞合成后期(G2期)的影響較小，除5 μmol/L DP組較未阻斷組G2期細胞數量增加有統計學意義(P lt;0.05)外，其余各組之間差異均無統計學意義(P gt;0.05); 在不含5-FU的培養液中培養24 h后，各組細胞周期中各期無明顯改變，各組之間比較差異均無統計學意義(P gt;0.05)。結論在胰腺癌細胞株Panc-1中，DP阻斷細胞膜上hENTs后，能顯著增強5-FU對胰腺癌細胞促凋亡作用及抑制胰腺癌細胞分裂增殖的作用，這種增強作用可能與阻斷hENTs后細胞內5-FU濃度提高有關，而與DP本身作用無關。

引用本文： 高毅明,周予民,宋海湖,范自平,劉浩. 阻斷胰腺癌平衡型核苷轉運載體對5-氟尿嘧啶誘導細胞凋亡及細胞周期改變的影響. 中國普外基礎與臨床雜志, 2011, 18(4): 396-400. doi: 復制

1.	劉勝利, 王晶敏, 鞠煌先, 等. 潘生丁抑制平衡型核苷轉運蛋白對5氟尿嘧啶在胰腺癌細胞內濃聚的影響 [J]. 中國藥科大學學報, 2003, 34(6): 544548.
2.	高毅明, 劉勝利. 阻斷胰腺癌細胞膜hENTs對氟尿嘧啶細胞毒性的影響 [J]. 現代醫學, 2006, 34(3): 149153.
3.	Tanaka M, Javle M, Dong X, et al. Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer [J]. Cancer, 2010, 116(22): 53255335.
4.	Santini D, Schiavon G, Vincenzi B, et al. Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC) [J]. Curr Cancer Drug Targets, 2010 Jun 25 [Epub ahead of print].
5.	Santini D, Vincenzi B, Fratto ME, et al. Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer [J]. J Cell Physiol, 2010, 223(2): 384388.
6.	Maréchal R, Mackey JR, Lai R, et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma [J]. Clin Cancer Res, 2009, 15(8): 29132919.
7.	Kong W, Engel K, Wang J. Mammalian nucleoside transporters [J]. Curr Drug Metab, 2004, 5(1): 6384.
8.	Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer [J]. Gastroenterology, 2009, 136(1): 187195.
9.	Michalski CW, Erkan M, Sauliunaite D, et al. Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer [J]. Br J Cancer, 2008, 99(5): 760767.
10.	Santini D, Vincenzi B, Fratto ME, et al. Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer [J]. J Cell Physiol, 2010, 223(2): 384388.
11.	馮燮林, 彭俊平, 李桂芳, 等. 胰腺癌區域灌注化療的并發癥及其防治 [J]. 中國普外基礎與臨床雜志, 2000, 7(6): 367369.
12.	Andersson R, Aho U, Nilsson BI, et al. Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions [J]. Scand J Gastroenterol, 2009, 44(7): 782786.
13.	MolinaArcas M, Marcé S, Villamor N, et al. Equilibrative nucleoside transporter2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells [J]. Leukemia, 2005, 19(1): 6468.
14.	Paproski RJ, Ng AM, Yao SY, et al. The role of human nucleoside transporters in uptake of 3’deoxy3’fluorothymidine [J]. Mol Pharmacol， 2008, 4(5): 13721380.
15.	Damaraju VL, Damaraju S, Young JD, et al. Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy [J]. Oncogene, 2003, 22(47): 75247536.
16.	King KM, Damaraju VL, Vickers MF, et al. A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems [J]. Mol Pharmacol, 2006, 69(1): 346353.
17.	Zhang J, Sun X, Smith KM, et al. Studies of nucleoside transporters using novel autofluorescent nucleoside probes [J]. Biochemistry, 2006, 45(4): 10871098.
18.	Ritzel MW, Ng AM, Yao SY, et al. Molecular identification and characterization of novel human and mouse concentrative Na+nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib) [J]. J Biol Chem, 2001, 276(4): 29142927.
19.	Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines [J]. Cancer Res, 1998, 58(19): 43494357.
20.	Yao SY, Sundaram M, Chomey EG, et al. Identification of Cys140 in helix 4 as an exofacial cysteine residue within the substratetranslocation channel of rat equilibrative nitrobenzylthioinosine (NBMPR)insensitive nucleoside transporter rENT2 [J]. Biochem J, 2001, 353(Pt 2): 387393.
21.	Goda AE, Yoshida T, Horinaka M, et al. Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole [J]. Oncogene, 2008, 27(24): 34353445.
22.	Schrier SM, van Tilburg EW, van der Meulen H, et al. Extracellular adenosineinduced apoptosis in mouse neuroblastoma cells: studies on involvement of adenosine receptors and adenosine uptake [J]. Biochem Pharmacol, 2001, 61(4): 417425.
23.	Kanno S, Hiura T, Ohtake T, et al. Characterization of resistance to cytosine arabinoside (AraC) in NALM6 human B leukemia cells [J]. Clin Chim Acta, 2007, 377(12): 144149.
24.	Visser F, Vickers MF, Ng AM, et al. Mutation of residue 33 of human equilibrative nucleoside transporters 1 and 2 alters sensitivity to inhibition of transport by dilazep and dipyridamole [J]. J Biol Chem, 2002, 277(1): 395401.
25.	Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment [J]. Lancet Oncol, 2002, 3(7): 415424.
26.	Gerstin KM, Dresser MJ, Giacomini KM. Specificity of human and rat orthologs of the concentrative nucleoside transporter, SPNT [J]. Am J Physiol Renal Physiol, 2002, 283(2): F344F349.

1. 劉勝利, 王晶敏, 鞠煌先, 等. 潘生丁抑制平衡型核苷轉運蛋白對5氟尿嘧啶在胰腺癌細胞內濃聚的影響 [J]. 中國藥科大學學報, 2003, 34(6): 544548.
2. 高毅明, 劉勝利. 阻斷胰腺癌細胞膜hENTs對氟尿嘧啶細胞毒性的影響 [J]. 現代醫學, 2006, 34(3): 149153.
3. Tanaka M, Javle M, Dong X, et al. Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer [J]. Cancer, 2010, 116(22): 53255335.
4. Santini D, Schiavon G, Vincenzi B, et al. Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC) [J]. Curr Cancer Drug Targets, 2010 Jun 25 [Epub ahead of print].
5. Santini D, Vincenzi B, Fratto ME, et al. Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer [J]. J Cell Physiol, 2010, 223(2): 384388.
6. Maréchal R, Mackey JR, Lai R, et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma [J]. Clin Cancer Res, 2009, 15(8): 29132919.
7. Kong W, Engel K, Wang J. Mammalian nucleoside transporters [J]. Curr Drug Metab, 2004, 5(1): 6384.
8. Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer [J]. Gastroenterology, 2009, 136(1): 187195.
9. Michalski CW, Erkan M, Sauliunaite D, et al. Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer [J]. Br J Cancer, 2008, 99(5): 760767.
10. Santini D, Vincenzi B, Fratto ME, et al. Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer [J]. J Cell Physiol, 2010, 223(2): 384388.
11. 馮燮林, 彭俊平, 李桂芳, 等. 胰腺癌區域灌注化療的并發癥及其防治 [J]. 中國普外基礎與臨床雜志, 2000, 7(6): 367369.
12. Andersson R, Aho U, Nilsson BI, et al. Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions [J]. Scand J Gastroenterol, 2009, 44(7): 782786.
13. MolinaArcas M, Marcé S, Villamor N, et al. Equilibrative nucleoside transporter2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells [J]. Leukemia, 2005, 19(1): 6468.
14. Paproski RJ, Ng AM, Yao SY, et al. The role of human nucleoside transporters in uptake of 3’deoxy3’fluorothymidine [J]. Mol Pharmacol， 2008, 4(5): 13721380.
15. Damaraju VL, Damaraju S, Young JD, et al. Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy [J]. Oncogene, 2003, 22(47): 75247536.
16. King KM, Damaraju VL, Vickers MF, et al. A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems [J]. Mol Pharmacol, 2006, 69(1): 346353.
17. Zhang J, Sun X, Smith KM, et al. Studies of nucleoside transporters using novel autofluorescent nucleoside probes [J]. Biochemistry, 2006, 45(4): 10871098.
18. Ritzel MW, Ng AM, Yao SY, et al. Molecular identification and characterization of novel human and mouse concentrative Na+nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib) [J]. J Biol Chem, 2001, 276(4): 29142927.
19. Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines [J]. Cancer Res, 1998, 58(19): 43494357.
20. Yao SY, Sundaram M, Chomey EG, et al. Identification of Cys140 in helix 4 as an exofacial cysteine residue within the substratetranslocation channel of rat equilibrative nitrobenzylthioinosine (NBMPR)insensitive nucleoside transporter rENT2 [J]. Biochem J, 2001, 353(Pt 2): 387393.
21. Goda AE, Yoshida T, Horinaka M, et al. Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole [J]. Oncogene, 2008, 27(24): 34353445.
22. Schrier SM, van Tilburg EW, van der Meulen H, et al. Extracellular adenosineinduced apoptosis in mouse neuroblastoma cells: studies on involvement of adenosine receptors and adenosine uptake [J]. Biochem Pharmacol, 2001, 61(4): 417425.
23. Kanno S, Hiura T, Ohtake T, et al. Characterization of resistance to cytosine arabinoside (AraC) in NALM6 human B leukemia cells [J]. Clin Chim Acta, 2007, 377(12): 144149.
24. Visser F, Vickers MF, Ng AM, et al. Mutation of residue 33 of human equilibrative nucleoside transporters 1 and 2 alters sensitivity to inhibition of transport by dilazep and dipyridamole [J]. J Biol Chem, 2002, 277(1): 395401.
25. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment [J]. Lancet Oncol, 2002, 3(7): 415424.
26. Gerstin KM, Dresser MJ, Giacomini KM. Specificity of human and rat orthologs of the concentrative nucleoside transporter, SPNT [J]. Am J Physiol Renal Physiol, 2002, 283(2): F344F349.

《中國普外基礎與臨床雜志》

阻斷胰腺癌平衡型核苷轉運載體對5-氟尿嘧啶誘導細胞凋亡及細胞周期改變的影響

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《中國普外基礎與臨床雜志》

阻斷胰腺癌平衡型核苷轉運載體對5-氟尿嘧啶誘導細胞凋亡及細胞周期改變的影響

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