Levitt Randy J, Pollak Michael
Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada, H3T 1E2.
Cancer Res. 2002 Dec 15;62(24):7372-6.
Cyclooxygenase (COX)-2 inhibitors demonstrate modest antineoplastic activity in experimental models of human malignancies, but little is known about factors that may confer resistance to their antiproliferative actions. We observed that fetal bovine serum antagonizes growth inhibition and G(1) arrest induced by two COX-2 inhibitors (NS-398 and celecoxib) on BxPC-3 pancreatic cancer cells. We investigated the hypothesis that insulin-like growth factor I (IGF-I), a major survival factor present in serum, mediates these effects. Treatment of BxPC-3 cells with 25 micro M celecoxib in 1% fetal bovine serum-containing medium for 48 h resulted in a approximately 40% decrease in cell viability. Coincubation of BxPC-3 cells with 25 micro M celecoxib and 50 ng/ml IGF-I resulted in complete attenuation of the celecoxib-associated decrease in cell viability. Cell cycle analysis revealed that this IGF-I-induced increase in cell viability was correlated with an IGF-I-induced inhibition of celecoxib-mediated G(1) arrest. Similar results were observed when another COX-2 inhibitor (50 micro M NS-398) was used. When IGF-binding protein-3 (an inhibitor of IGF-I bioactivity) was added in combination with 25 micro M celecoxib, enhanced growth inhibition was observed (approximately 60% decrease in cell viability). Treatment of BxPC-3 cells with a higher dose (50 micro M) of celecoxib for 24 h resulted in the induction of apoptosis, as assayed by flow cytometry and poly(ADP-ribose) polymerase cleavage. Addition of 50 ng/ml IGF-I resulted in a complete attenuation of celecoxib-induced apoptosis. The protection from celecoxib-induced apoptosis by IGF-I correlated with an increase in the levels of the activated antiapoptotic protein Akt. These results suggest that alterations of IGF-I levels or IGF-I receptor signal transduction modulate the antineoplastic actions of COX-2 inhibitors.
环氧化酶（COX）-2抑制剂在人类恶性肿瘤实验模型中显示出适度的抗肿瘤活性，但对于可能导致其抗增殖作用产生耐药性的因素知之甚少。我们观察到胎牛血清可拮抗两种COX-2抑制剂（NS-398和塞来昔布）对BxPC-3胰腺癌细胞诱导的生长抑制和G(1)期阻滞。我们研究了这样一个假设，即胰岛素样生长因子I（IGF-I）作为血清中一种主要的存活因子，介导了这些效应。在含1%胎牛血清的培养基中用25微摩尔/升塞来昔布处理BxPC-3细胞48小时，导致细胞活力下降约40%。将BxPC-3细胞与25微摩尔/升塞来昔布和50纳克/毫升IGF-I共同孵育，可完全消除塞来昔布相关的细胞活力下降。细胞周期分析显示，这种IGF-I诱导的细胞活力增加与IGF-I诱导的塞来昔布介导的G(1)期阻滞抑制相关。当使用另一种COX-2抑制剂（50微摩尔/升NS-398）时，观察到了类似的结果。当将IGF结合蛋白-3（一种IGF-I生物活性抑制剂）与25微摩尔/升塞来昔布联合添加时，观察到生长抑制增强（细胞活力下降约60%）。用更高剂量（50微摩尔/升）的塞来昔布处理BxPC-3细胞24小时，通过流式细胞术和聚（ADP-核糖）聚合酶裂解检测，导致细胞凋亡的诱导。添加50纳克/毫升IGF-I可完全消除塞来昔布诱导的细胞凋亡。IGF-I对塞来昔布诱导的细胞凋亡的保护作用与活化的抗凋亡蛋白Akt水平的增加相关。这些结果表明，IGF-I水平或IGF-I受体信号转导的改变可调节COX-2抑制剂的抗肿瘤作用。
