Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model
Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model
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DOI：
10.1002/ijc.10168
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发表时间：
2002-03-10
影响因子：
6.4
通讯作者：
Golub, LM
中科院分区：
文献类型：
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作者：
Lokeshwar, BL;Selzer, MG;Golub, LM
抗生素形式的四环素在某些肿瘤模型中显示出抗肿瘤活性。然而，它们在体内的低效率和相关的发病率限制了它们在癌症治疗中的长期应用。本报告评价了多西环素(DC)和非抗菌化学修饰的四环素(CMTs)治疗前列腺癌的疗效。DC和几种CMTs在体外均能抑制前列腺癌细胞的增殖。有些CMT的效力明显强于DC。其中6-脱氧，6-去甲基，4-脱二甲氨基四环素(CMT-3，Col-3)是最有效的抑制药物，其半数抑制量[GI(50)]小于或等于5.0µg/ml。肿瘤细胞暴露于CMT-3可诱导细胞凋亡和坏死。在经CMT-3处理的细胞中，还观察到线粒体去极化和反应性羟基自由基水平的增加。在CMT-3和DC处理的细胞中，观察到G(0)/G(1)区的细胞周期停滞。DC和CMTs也能抑制肿瘤细胞的体外侵袭能力，从10%(CMT-6)到90%(CMT-3)。CMT-3和DC均能减少基质金属蛋白酶(MMP2)、基质金属蛋白酶组织抑制因子(TIMP)-1和TIMP-2的分泌，抑制MMPs的分泌，其中CMT-3抑制作用更强。每日灌胃DC和CMT-3可抑制Dunning Mat LyLu大鼠前列腺癌的生长和转移。观察到肿瘤生长(27-35%)和肺转移减少(28.9+/-15.4个/动物[CMT-3治疗]和43.6+/-18.8个/动物[DC治疗]和59313.9[对照]；p<；0.01]。预先给药7天后，肿瘤生长延缓(27+/-9.3%，p<；0.05)，转移减少(58+/-8%)，肿瘤发生率降低(55+/-9%CMT-3治疗)。在任何动物身上都没有观察到明显的药物引起的发病率。这些结果，以及最近结束的一项临床试验，表明CMT-3可能被用作口服无毒药物来治疗转移性前列腺癌和其他癌症。(C)2002年Wiley-Liss，Inc.
Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] less than or equal to 5.0 mug/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G(0)/G(1) compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 593 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9% CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers. (C) 2002 Wiley-Liss, Inc.