Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G.
Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G.
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DOI：
10.1158/1535-7163.mct-09-0758
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发表时间：
2009-12
影响因子：
5.7
通讯作者：
Piazza GA
中科院分区：
文献类型：
--
作者：
Tinsley HN;Gary BD;Keeton AB;Zhang W;Abadi AH;Reynolds RC;Piazza GA
舒林酸显示出有希望的抗肿瘤活性，但环氧化酶（考克斯）抑制的毒性限制了其用于化学预防。以前的报道表明，其抗癌特性可能归因于COX-独立的机制，尽管替代靶点还没有很好地定义。我们发现舒林酸硫化物（SS）诱导人乳腺肿瘤细胞凋亡并抑制其生长，IC 50值为60-85 μM。在相同浓度范围内，SS抑制肿瘤细胞裂解物中cGMP的水解，但不影响cAMP的水解。SS不诱导正常人乳腺上皮细胞（HMEC）的凋亡，也不抑制HMEC裂解物中PDE的活性。SS增加乳腺癌细胞内cGMP水平和激活蛋白激酶G，但不增加HMEC。鸟苷酸环化酶（GC）激活剂NOR-3和cGMP PDE抑制剂trequinsin和MY 5445显示出与SS相似的生长抑制活性，但腺苷酸环化酶激活剂forskolin和其他PDE抑制剂没有效果。此外，GC激活增加肿瘤细胞对SS的敏感性，而GC抑制降低敏感性。通过比较乳腺肿瘤细胞与HMEC中PDE同工酶谱并确定重组PDE同工酶对SS的敏感性，发现PDE 5在乳腺肿瘤细胞中过表达并被SS选择性抑制。通过分子模拟揭示了SS与PDE 5催化结构域的结合机制。这些数据表明，PDE 5抑制是负责乳腺肿瘤细胞生长抑制和诱导细胞凋亡活性的SS，并可能有助于舒林酸的化学预防性能。
Sulindac displays promising antineoplastic activity, but toxicities from cyclooxygenase (COX) inhibition limit its use for chemoprevention. Previous reports suggest that its anticancer properties may be attributed to a COX-independent mechanism, although alternative targets have not been well defined. Here we show that sulindac sulfide (SS) induces apoptosis and inhibits the growth of human breast tumor cells with IC50 values of 60-85 μM. Within the same concentration range, SS inhibited cGMP hydrolysis in tumor cell lysates, but did not affect cAMP hydrolysis. SS did not induce apoptosis of normal human mammary epithelial cells (HMEC), nor did it inhibit PDE activity in HMEC lysates. SS increased intracellular cGMP levels and activated protein kinase G in breast tumor cells, but not HMEC. The guanylyl cyclase (GC) activator, NOR-3, and cGMP PDE inhibitors, trequinsin and MY5445, displayed similar growth inhibitory activity as SS, but the adenylyl cyclase activator, forskolin, and other PDE inhibitors had no effect. Moreover, GC activation increased the sensitivity of tumor cells to SS, while GC inhibition reduced sensitivity. By comparing PDE isozyme profiles in breast tumor cells with HMEC and determining the sensitivity of recombinant PDE isozymes to SS, PDE5 was found to be overexpressed in breast tumor cells and selectively inhibited by SS. The mechanism of SS binding to the catalytic domain of PDE5 was revealed by molecular modeling. These data suggest that PDE5 inhibition is responsible for the breast tumor cell growth inhibitory and apoptosis inducing activity of SS and may contribute to the chemopreventive properties of sulindac.