Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells.
Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells.
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环氧酶-2抑制剂Celecoxib在人乳腺癌细胞中的生长抑制作用的基础机制。
DOI：
10.1186/bcr1019
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发表时间：
2005
影响因子：
7.4
通讯作者：
Mukherjee, P
中科院分区：
文献类型：
--
作者：
Basu, GD;Pathangey, LB;Tinder, TL;Gendler, SJ;Mukherjee, P
环加氧酶 (COX)-2 抑制剂作为抗癌药物正在被广泛研究。在本研究中，我们评估了高选择性 COX-2 抑制剂塞来昔布影响两种不同侵袭性人类乳腺癌细胞系肿瘤生长的机制。在体外用不同浓度的塞来昔布处理 MDA-MB-231（高侵袭性）和 MDA-MB-468（中度侵袭性）细胞系，并通过评估细胞增殖、凋亡、细胞周期停滞和血管生成拟态来监测该药物对细胞生长和血管生成的影响。 MDA-MB-231细胞系的体外结果在小鼠异种移植模型的体内得到进一步证实。侵袭性高的 MDA-MB-231 细胞比侵袭性较小的 MDA-MB-468 细胞表达更高水平的 COX-2。塞来昔布治疗抑制 COX-2 活性（前列腺素 E2 分泌表明），并导致两种乳腺癌细胞系显着生长停滞。在高侵袭性 MDA-MB-231 细胞中，塞来昔布诱导生长停滞的机制是诱导细胞凋亡，与蛋白激酶 B/Akt 激活减少以及随后的 caspase 3 和 7 激活有关。在低侵袭性 MDA-MB-468 细胞中，生长停滞是细胞周期在 G0/G1 检查点停滞的结果。在 MDA-MB-468 细胞中添加外源性前列腺素 E2 可逆转塞来昔布诱导的生长抑制，但在 MDA-MB-231 细胞中则不然。此外，与高表达 COX-2 的 MDA-MB-231 细胞相比，MDA-MB-468 细胞在体外形成的细胞外基质相关微血管通道明显更少。塞来昔布治疗不仅抑制细胞生长和血管通道形成，而且降低血管内皮生长因子水平。体外研究结果证实了小鼠异种移植模型的体内数据，其中每日给予塞来昔布可显着减少 MDA-MB-231 细胞的肿瘤生长，这与肿瘤块中血管形成的减少和坏死的增加有关。塞来昔布诱导人乳腺癌细胞生长抑制的不同分子机制取决于 COX-2 表达水平和所检查细胞系的侵袭潜力。数据表明，COX-2 不仅在癌细胞生长中发挥作用，而且还通过调节血管内皮生长因子的水平激活血管生成途径。
Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor.
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影响因子：
8
作者：
Denkert, C;Fürstenberg, A;Hauptmann, S
通讯作者：
Hauptmann, S
影响因子：
3.5
作者：
BENAV, P;CROFFORD, LJ;HLA, T
通讯作者：
HLA, T
影响因子：
4.8
作者：
Arico, S;Pattingre, S;Ogier-Denis, E
通讯作者：
Ogier-Denis, E
DOI：
10.1073/pnas.2535911100
发表时间：
2004-01-13
影响因子：
11.1
作者：
Chang, SH;Liu, CH;Hla, T
通讯作者：
Hla, T
影响因子：
64.5
作者：
Datta, SR;Dudek, H;Greenberg, ME
通讯作者：
Greenberg, ME