Inhibition of cyclooxygenase (COX)-2 expression by tet-inducible COX-2 antisense cDNA in hormone-refractory prostate cancer significantly slows tumor growth and improves efficacy of chemotherapeutic drugs
Inhibition of cyclooxygenase (COX)-2 expression by tet-inducible COX-2 antisense cDNA in hormone-refractory prostate cancer significantly slows tumor growth and improves efficacy of chemotherapeutic drugs
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DOI：
10.1158/1078-0432.ccr-04-1208
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发表时间：
2004-12-01
影响因子：
11.5
通讯作者：
Lokeshwar, BL
中科院分区：
文献类型：
--
作者：
Dandekar, DS;Lokeshwar, BL
目的：环氧合酶(COX)-2的过度表达与多种恶性肿瘤的发生发展有关；COX-2在前列腺癌中的作用尚不清楚。利用Tet诱导的COX-2反义表达系统，研究COX-2在雄激素耐药前列腺癌生长和化疗反应中的作用。实验设计：将多西环素可诱导启动子控制下的COX-2反义cDNA导入前列腺癌PC-3ML细胞。分析了有无多西环素对细胞生长、凋亡和化疗敏感性的调节作用。研究了两种细胞毒性药物COL-3[化学修饰的tetracycline-3-(6demethyl-6-deoxy-4-dedimethylamino-tetracycline)I和泰索帝(多西紫杉醇)]在肿瘤异种移植瘤中的发病率、生长速度和对两种药物的反应。结果：条件性抑制COX-2可抑制PC-3ML细胞增殖，降低AKT磷酸化水平，减少G(0)-G(1)期停滞，增加细胞凋亡率和caspase-3活性。抑制COX-2在体外可使Bax蛋白表达增加，Bcl一x蛋白表达降低(L)。COX-2反义表达的PC-3ML肿瘤与未转染组和载体对照组相比，生长延迟了57%。在荷瘤小鼠中，口服Col-3(40 mg/kg，口服)或泰索帝(2.3 mg/kg，每周3次)进一步减缓了肿瘤的生长(分别为65%和94%)。与对照组相比，COX-2反义组肿瘤细胞凋亡率增加8倍，肿瘤微血管密度降低3倍。结论：COX-2在前列腺癌中的结构性表达具有血管生成和细胞保护作用。抑制肿瘤细胞COX-2足以增强前列腺癌的化疗反应。
Purpose: Overexpression of the proinflammatory enzyme cyclooxygenase (COX)-2 is associated with the progression of various malignancies; the role of COX-2 in prostate cancer is less clear. The significance of COX-2 in prostate cancer growth and response to chemotherapy was investigated in an androgen-refractory prostate cancer cell line using a Tet-inducible antisense COX-2 expression system.Experimental Design: An antisense COX-2 cDNA construct under the control of a doxycycline- inducible promoter was transfected into a prostate cancer cell line, PC-3ML. Modulations of cell growth, apoptosis, and chemosensitivity in the presence or absence of doxycycline were analyzed. Tumor incidence, growth rate, and response to two cytotoxic drugs, COL-3 [chemically modified tetracycline-3-(6demethyl-6-deoxy-4-dedimethylamino-tetracycline)I and Taxotere (docetaxel), were investigated in tumor xenografts. Apoptotic incidences and tumor microvessel density in tumors were determined by immunohistochemistry.Results: Conditional suppression of COX-2 in PC-3ML caused reduced cell proliferation, decreased levels of phosphorylated AKT, G(0)-G(1) arrest, and increased apoptosis and caspase-3 activity. Suppression of COX-2 increased Bax protein and decreased Bcl-x(L) protein in vitro. COX-2 antisense-expressing PC-3ML tumors showed a 57% growth delay compared with nontransfected or vector controls. Oral administration of COL-3 (40 mg/kg, oral gavage) or Taxotere (2.3 mg/kg, intraperitoneally; 3 X per week) in tumor-bearing mice further slowed tumor growth (65% and similar to94%, respectively). Compared with the control group, the occurrence of apoptosis in antisense COX-2 tumors was eight times higher, and the tumor microvessel density was three times lower.Conclusions: These results provide direct evidence that constitutive expression of COX-2 in prostate cancer has both angiogenic and cytoprotective functions. Suppression of tumor cell COX-2 is sufficient to enhance chemotherapy response in prostate cancer.