Nitric oxide-donating aspirin inhibits the growth of pancreatic cancer cells through redox-dependent signaling.
Nitric oxide-donating aspirin inhibits the growth of pancreatic cancer cells through redox-dependent signaling.
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DOI：
10.1016/j.canlet.2008.08.006
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发表时间：
2009-01-18
期刊：
影响因子：
9.7
通讯作者：
Rigas, Basil
中科院分区：
文献类型：
--
作者：
Zhou, Hui;Huang, Liqun;Sun, Yu;Rigas, Basil
The novel chemopreventive nitric oxide-donating aspirin (NO-ASA) prevents nearly 90% of ductal adenocarcinomas in a animal tumor model. To decipher the mechanism of this effect, we studied in BxPC-3 human pancreatic cancer cells the sequence of signaling events leading from NO-ASA treatment to cell growth inhibition. NO-ASA inhibited the growth of BxPC-3 cells (IC50 = 13 μM), by inhibiting proliferation modestly and inducing apoptosis, necrosis and G1/S cell cycle block. At 15 min of treatment with NO-ASA, the intracellular levels of reactive oxygen species (ROS) began increasing (peak at 8 h, baseline levels by 24 h). ROS activated almost immediately in a time- and concentration-dependent manner the MAPK pathways p38, ERK, and JNK (their activation was abrogated by the antioxidant N-acetylcysteine). MAPK activation induced p21cip-1, which suppressed the levels of cyclin D1 that controls G1/S cell cycle transition. NO-ASA induced COX-2 expression starting 90 min after p21cip-1 was induced. When COX-2 expression was knocked-down using siRNA against cox-2, the expression of p21cip-1 was induced by NO-ASA, regardless of the level of expression of COX-2, suggesting a marginal, if any, role for COX-2 in the growth inhibitory effect of NO-ASA. These findings along with the temporal sequence of individual changes indicate a signaling sequence that involves ROS → MAPKs → p21cip-1 → cyclin D1 → cell death. Our findings establish the critical role of ROS as proximal signaling molecules in the action of anticancer compounds and may be useful in designing mechanism-driven approaches to cancer control.
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DOI：
10.1073/pnas.0506893102
发表时间：
2005-11-22
影响因子：
11.1
作者：
Gao, JJ;Liu, XP;Rigas, B
通讯作者：
Rigas, B
影响因子：
4.8
作者：
Zahner, G;Wolf, G;Stahl, RAK
通讯作者：
Stahl, RAK
影响因子：
7.3
作者：
Penning, TD;Talley, JJ;Isakson, PC
通讯作者：
Isakson, PC
影响因子：
5.8
作者：
Frein, D;Schildknecht, S;Ullrich, V
通讯作者：
Ullrich, V
DOI：
10.1124/jpet.105.091363
发表时间：
2006-01-01
影响因子：
3.5
作者：
Hundley, TR;Rigas, B
通讯作者：
Rigas, B