Piazza G A, Rahm A L, Krutzsch M, Sperl G, Paranka N S, Gross P H, Brendel K, Burt R W, Alberts D S, Pamukcu R
Cell Pathways, Inc., Denver, Colorado 80012-4526, USA.
Cancer Res. 1995 Jul 15;55(14):3110-6.
The nonsteroidal anti-inflammatory drug sulindac is known to inhibit chemical carcinogenesis in rodent models and cause regression of adenomas in patients with adenomatous polyposis coli. Sulindac is a prodrug that is metabolized to a pharmacologically active sulfide derivative that potently inhibits prostaglandin synthesis. Recent studies, however, have shown that a sulfone derivative of sulindac, which essentially lacks prostaglandin synthesis inhibitory activity, also inhibits chemical carcinogenesis, suggesting that reduction of prostaglandin levels is not necessary for the antineoplastic activity of this class of drugs. Both sulindac sulfide and the sulfone inhibit the growth of cultured tumor cells, although the cellular mechanism(s) responsible for the antineoplastic activity of sulindac derivatives is unknown. In this study, we investigated the effects of sulindac sulfide and sulfone on the proliferation, differentiation, and apoptosis of HT-29 human colon carcinoma cells. Sulindac sulfide and sulfone significantly reduced cell number in both preconfluent and confluent cultures of HT-29 cells with the sulfide showing approximately 4-fold greater potency. In addition to HT-29 cells, both drugs inhibited the growth of a variety of tumor cell lines derived from other tissues, as well as normal epithelial cells and fibroblasts. Neither sulindac sulfide nor sulfone inhibited cell proliferation under conditions where the drugs were growth inhibitory. Only under specific conditions involving mitogenic stimulation did sulindac sulfide and sulfone cause cell cycle arrest. Neither sulindac sulfide nor the sulfone induced differentiation of HT-29 cells, but both drugs strongly induced apoptosis. The apoptotic response to sulindac sulfide and sulfone was both time- and dose-dependent and involved a mechanism independent of their inhibitory effect on cell cycle progression. These data suggest that apoptosis is responsible for the cell growth inhibitory activity of sulindac sulfide and sulfone and represents a potential mechanism for the antineoplastic activity of these drugs.
已知非甾体抗炎药舒林酸可抑制啮齿动物模型中的化学致癌作用，并使家族性腺瘤性息肉病患者的腺瘤消退。舒林酸是一种前体药物，可代谢为具有药理活性的硫化物衍生物，该衍生物能有效抑制前列腺素合成。然而，最近的研究表明，舒林酸的砜衍生物基本缺乏前列腺素合成抑制活性，但同样能抑制化学致癌作用，这表明降低前列腺素水平并非这类药物抗肿瘤活性所必需。舒林酸硫化物和砜均可抑制培养的肿瘤细胞生长，尽管尚不清楚舒林酸衍生物抗肿瘤活性的细胞机制。在本研究中，我们研究了舒林酸硫化物和砜对HT-29人结肠癌细胞增殖、分化和凋亡的影响。舒林酸硫化物和砜显著减少了HT-29细胞预汇合和汇合培养中的细胞数量，其中硫化物的效力约高4倍。除HT-29细胞外，这两种药物还抑制了源自其他组织的多种肿瘤细胞系以及正常上皮细胞和成纤维细胞的生长。在药物具有生长抑制作用的条件下，舒林酸硫化物和砜均未抑制细胞增殖。只有在涉及促有丝分裂刺激的特定条件下，舒林酸硫化物和砜才会导致细胞周期停滞。舒林酸硫化物和砜均未诱导HT-29细胞分化，但两种药物均强烈诱导凋亡。对舒林酸硫化物和砜的凋亡反应具有时间和剂量依赖性，且涉及一种独立于其对细胞周期进程抑制作用的机制。这些数据表明，凋亡是舒林酸硫化物和砜细胞生长抑制活性的原因，也是这些药物抗肿瘤活性的潜在机制。
