• 大連醫(yī)科大學(xué)附屬第一醫(yī)院普外科(遼寧大連 116011);

目的評(píng)估鋅原卟啉(ZnPP)Ⅸ對(duì)肝癌耐藥細(xì)胞株化療藥物敏感性及其表達(dá)血紅素加氧酶-1（heme oxygenase,HO-1）和谷胱甘肽-S-轉(zhuǎn)移酶-π（glutathione-S-transferase-π，GST-π）的影響，探討ZnPP Ⅸ作為化療耐藥逆轉(zhuǎn)劑的可能性及相關(guān)作用機(jī)理。方法①ZnPP Ⅸ作用于肝癌耐藥細(xì)胞株Bel/Fu后，應(yīng)用MTT法檢測(cè)阿霉素、絲裂霉素及5-氟尿嘧啶的半數(shù)抑制濃度（IC50）。②不同濃度ZnPP Ⅸ作用于Bel/Fu細(xì)胞后，應(yīng)用RT-PCR法檢測(cè)細(xì)胞HO-1及GST-π mRNA的表達(dá)量。結(jié)果ZnPP Ⅸ作用于Bel/Fu細(xì)胞24 h后，各化療藥物的IC50均明顯降低（P lt;0.05）； HO-1 mRNA及GST-π mRNA的表達(dá)量顯著降低(P lt;0.01)，且均呈劑量依賴趨勢(shì)（P lt;0.01）。結(jié)論ZnPP Ⅸ通過(guò)抑制HO-1和GST-π的表達(dá)，使肝癌耐藥細(xì)胞株的化療敏感性增高。ZnPP Ⅸ可作為一種潛在的化療耐藥逆轉(zhuǎn)劑。

引用本文： 張雋開,王忠裕,鞏鵬,羅海峰,程雷. ZnPP Ⅸ對(duì)肝癌耐藥細(xì)胞株Bel/Fu表達(dá)HO-1、GST-π及化療敏感性的影響. 中國(guó)普外基礎(chǔ)與臨床雜志, 2011, 18(5): 503-506. doi: 復(fù)制

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1. Motterlini R, Foresti R, Bassi R, et al. Endothelial heme oxygenase1 induction by hypoxia. Modulation by inducible nitricoxide synthase and Snitrosothiols [J]. J Biol Chem, 2000, 275(18): 1361313620.
2. Goodman AI, Choudhury M, da Silva JL, et al. Overexpression of the heme oxygenase gene in renal cell carcinoma [J]. Proc Soc Exp Biol Med, 1997, 214(1): 5461.
3. Maines MD, Abrahamsson PA.Expression of heme oxygenase1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution [J]. Urology, 1996, 47(5): 727733.
4. Reiter TA, Demple B. Carbon monoxide mediates protection against nitric oxide toxicity in HeLa cells [J]. Free Radic Biol Med, 2005, 39(8): 10751088.
5. Wagener FA, da Silva JL, Farley T, et al. Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression [J]. J Pharmacol Exp Ther， 1999， 291(1): 416423.
6. 張黎, 程力, 李更生, 等. 血紅素氧化酶1在大鼠肝移植中保護(hù)作用的研究 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2008, 15(9): 665 670.
7. CordonCardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (Pglycoprotein) in human normal and tumor tissues [J]. J Histochem Cytochem, 1990, 38(9): 12771287.
8. 魏學(xué)明, 顧國(guó)利, 任力, 等. 多藥耐藥基因產(chǎn)物在胃癌組織中的表達(dá)及意義 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2009, 16(12): 10001004.
9. Berberat PO, Dambrauskas Z, Gulbinas A, et al. Inhibition of heme oxygenase1 increases responsiveness of pancreatic cancer cells to anticancer treatment [J]. Clin Cancer Res, 2005, 11(10): 37903798．.
10. 張雋開, 王忠裕, 丁大鵬， 等. 血紅素加氧酶對(duì)肝癌耐藥細(xì)胞株Bel/Fu化療敏感性的影響 [J]. 中華腫瘤防治雜志, 2009, 16(13): 990993．.
11. Yu DS, Lin JC, Hsieh DS, et al. Modulation of MDR1 gene by MIF and GSTpi with drug resistance generation in hormone independent prostate cancer [J]. Arch Androl, 2006, 52(4): 283291.
12. 薛軍, 支學(xué)軍, 屈明, 等. 胃癌及食管癌中腫瘤耐藥標(biāo)志物P糖蛋白和谷胱甘肽轉(zhuǎn)移酶表達(dá)的研究 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2002, 9(5): F2.
13. Dirven HA, Dictus EL, Broeders NL, et al. The role of human glutathione Stransferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa [J]. Cancer Res, 1995, 55(8): 17011706.
14. Kuroda H, Sugimoto T, Ueda K, et al. Different drug sensitivity in two neuroblastoma cell lines established from the same patient before and after chemotherapy [J]. Int J Cancer, 1991, 47(5): 732737.
15. Sato K, Satoh K, Tsuchida S, et al. Specific expression of glutathione Stransferase Pi forms in (pre)neoplastic tissues: their properties and functions [J]. Tohoku J Exp Med, 1992, 168(2): 97103.
16. Hirai K, Sasahira T, Ohmori H, et al. Inhibition of heme oxygenase1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice [J]. Int J Cancer, 2007, 120(3): 500505.
17. Tanaka S, Akaike T, Fang J, et al. Antiapoptotic effect of haem oxygenase1 induced by nitric oxide in experimental solid tumour [J]. Br J Cancer, 2003, 88(6): 902909.
18. Yokoyama S, Mita S, Okabe A, et al. Prediction of radiosensitivity in human esophageal squamous cell carcinomas with heme oxygenase1: a clinicopathological and immunohistochemical study [J]. Oncol Rep, 2001, 8(2): 355358.
  1. 1. Motterlini R, Foresti R, Bassi R, et al. Endothelial heme oxygenase1 induction by hypoxia. Modulation by inducible nitricoxide synthase and Snitrosothiols [J]. J Biol Chem, 2000, 275(18): 1361313620.
  2. 2. Goodman AI, Choudhury M, da Silva JL, et al. Overexpression of the heme oxygenase gene in renal cell carcinoma [J]. Proc Soc Exp Biol Med, 1997, 214(1): 5461.
  3. 3. Maines MD, Abrahamsson PA.Expression of heme oxygenase1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution [J]. Urology, 1996, 47(5): 727733.
  4. 4. Reiter TA, Demple B. Carbon monoxide mediates protection against nitric oxide toxicity in HeLa cells [J]. Free Radic Biol Med, 2005, 39(8): 10751088.
  5. 5. Wagener FA, da Silva JL, Farley T, et al. Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression [J]. J Pharmacol Exp Ther， 1999， 291(1): 416423.
  6. 6. 張黎, 程力, 李更生, 等. 血紅素氧化酶1在大鼠肝移植中保護(hù)作用的研究 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2008, 15(9): 665 670.
  7. 7. CordonCardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (Pglycoprotein) in human normal and tumor tissues [J]. J Histochem Cytochem, 1990, 38(9): 12771287.
  8. 8. 魏學(xué)明, 顧國(guó)利, 任力, 等. 多藥耐藥基因產(chǎn)物在胃癌組織中的表達(dá)及意義 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2009, 16(12): 10001004.
  9. 9. Berberat PO, Dambrauskas Z, Gulbinas A, et al. Inhibition of heme oxygenase1 increases responsiveness of pancreatic cancer cells to anticancer treatment [J]. Clin Cancer Res, 2005, 11(10): 37903798．.
  10. 10. 張雋開, 王忠裕, 丁大鵬， 等. 血紅素加氧酶對(duì)肝癌耐藥細(xì)胞株Bel/Fu化療敏感性的影響 [J]. 中華腫瘤防治雜志, 2009, 16(13): 990993．.
  11. 11. Yu DS, Lin JC, Hsieh DS, et al. Modulation of MDR1 gene by MIF and GSTpi with drug resistance generation in hormone independent prostate cancer [J]. Arch Androl, 2006, 52(4): 283291.
  12. 12. 薛軍, 支學(xué)軍, 屈明, 等. 胃癌及食管癌中腫瘤耐藥標(biāo)志物P糖蛋白和谷胱甘肽轉(zhuǎn)移酶表達(dá)的研究 [J]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2002, 9(5): F2.
  13. 13. Dirven HA, Dictus EL, Broeders NL, et al. The role of human glutathione Stransferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa [J]. Cancer Res, 1995, 55(8): 17011706.
  14. 14. Kuroda H, Sugimoto T, Ueda K, et al. Different drug sensitivity in two neuroblastoma cell lines established from the same patient before and after chemotherapy [J]. Int J Cancer, 1991, 47(5): 732737.
  15. 15. Sato K, Satoh K, Tsuchida S, et al. Specific expression of glutathione Stransferase Pi forms in (pre)neoplastic tissues: their properties and functions [J]. Tohoku J Exp Med, 1992, 168(2): 97103.
  16. 16. Hirai K, Sasahira T, Ohmori H, et al. Inhibition of heme oxygenase1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice [J]. Int J Cancer, 2007, 120(3): 500505.
  17. 17. Tanaka S, Akaike T, Fang J, et al. Antiapoptotic effect of haem oxygenase1 induced by nitric oxide in experimental solid tumour [J]. Br J Cancer, 2003, 88(6): 902909.
  18. 18. Yokoyama S, Mita S, Okabe A, et al. Prediction of radiosensitivity in human esophageal squamous cell carcinomas with heme oxygenase1: a clinicopathological and immunohistochemical study [J]. Oncol Rep, 2001, 8(2): 355358.