Lim J T, Piazza G A, Han E K, Delohery T M, Li H, Finn T S, Buttyan R, Yamamoto H, Sperl G J, Brendel K, Gross P H, Pamukcu R, Weinstein I B
Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Biochem Pharmacol. 1999 Oct 1;58(7):1097-107. doi: 10.1016/s0006-2952(99)00200-2.
We examined the activity of two metabolites of sulindac (a nonsteroidal anti-inflammatory drug), sulindac sulfide and sulindac sulfone (exisulind, Prevatec), and a novel highly potent analog of exisulind (CP248) on a series of human prostate epithelial cell lines. Marked growth inhibition was seen with the BPH-1, LNCaP, and PC3 cell lines with IC50 values of about 66 microM, 137 microM, and 64 nM for sulindac sulfide, exisulind, and CP248, respectively. DNA flow cytometry and 4',6'-diamido-2-phenylindole (DAPI) staining indicated that these three compounds also induced apoptosis in all of these cell lines. Similar growth inhibition also was seen with the PrEC normal human prostate epithelial cell line, but these cells were resistant to induction of apoptosis at concentrations up to 300 microM, 1 mM, and 750 nM of sulindac sulfide, exisulind, and CP248, respectively. Derivatives of LNCaP cells that stably overexpress bcl-2 remained sensitive to growth inhibition and induction of apoptosis by these compounds. In vitro enzyme assays indicated that despite its high potency in inhibiting growth and inducing apoptosis, CP248, like exisulind, lacked cyclooxygenase (COX-1 and COX-2) inhibitory activity even at concentrations up to 10 mM. Moreover, despite variations of COX-1 and COX-2 expression, the three benign and malignant prostate cell lines showed similar sensitivity to growth inhibition and induction of apoptosis by these three compounds. Therefore, sulindac derivatives can cause growth inhibition and induce apoptosis in human prostate cancer cells by a COX-1 and -2 independent mechanism, and this occurs irrespective of androgen sensitivity or increased expression of bcl-2. These compounds may be useful in the prevention and treatment of human prostate cancer.
我们研究了舒林酸（一种非甾体抗炎药）的两种代谢产物——舒林酸硫化物和舒林酸砜（依西美坦，Prevatec），以及一种新型高效依西美坦类似物（CP248）对一系列人前列腺上皮细胞系的活性。在BPH - 1、LNCaP和PC3细胞系中观察到明显的生长抑制，舒林酸硫化物、依西美坦和CP248的IC50值分别约为66微摩尔、137微摩尔和64纳摩尔。DNA流式细胞术和4',6'-二脒基-2-苯基吲哚（DAPI）染色表明，这三种化合物在所有这些细胞系中也诱导了细胞凋亡。在PrEC正常人前列腺上皮细胞系中也观察到了类似的生长抑制，但这些细胞分别对高达300微摩尔、1毫摩尔和750纳摩尔的舒林酸硫化物、依西美坦和CP248诱导的细胞凋亡具有抗性。稳定过表达bcl-2的LNCaP细胞衍生物对这些化合物诱导的生长抑制和细胞凋亡仍保持敏感。体外酶活性测定表明，尽管CP248在抑制生长和诱导细胞凋亡方面具有高效性，但与依西美坦一样，即使在浓度高达10毫摩尔时也缺乏环氧化酶（COX - 1和COX - 2）抑制活性。此外，尽管COX - 1和COX - 2表达存在差异，但三种良性和恶性前列腺细胞系对这三种化合物诱导的生长抑制和细胞凋亡表现出相似的敏感性。因此，舒林酸衍生物可通过COX - 1和 - 2独立机制导致人前列腺癌细胞生长抑制并诱导细胞凋亡，且这种情况与雄激素敏感性或bcl-2表达增加无关。这些化合物可能对人类前列腺癌的预防和治疗有用。
