Shaik Madhu Sudhan, Chatterjee Abhijit, Singh Mandip
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, USA.
Clin Cancer Res. 2004 Feb 15;10(4):1521-9. doi: 10.1158/1078-0432.ccr-0902-03.
The objectives of this study were to evaluate the effect of a cyclooxygenase (COX)-2 inhibitor, nimesulide, on the growth inhibition of s.c. human lung A549 adenocarcinoma tumors and to assess the effect of nimesulide on the expression of COX-2 and peroxisome proliferator-activated receptor (PPAR)-gamma in lung tumors harvested from mice.
Female nu/nu mice were xenografted with s.c. A549 lung tumors, and 1 day after tumor implantation, the mice were fed with a diet containing nimesulide at 250-1500 ppm doses. Tumor dimensions were monitored twice weekly, and tumor samples isolated from mice were used to determine prostaglandin E(2) (PGE(2)) levels by enzyme immunoassay, expression of COX-2 and PPAR-gamma by Western blotting and immunohistochemistry. Furthermore, the induction of apoptosis in tumor specimens was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling staining.
Nimesulide treatment showed a dose-dependent growth-inhibitory effect of A549 tumors with a maximum of 77.7% inhibition at 1500 ppm of nimesulide. Western blotting experiments showed similar expression of COX-2 in both control and nimesulide (250-1500 ppm)-treated mice tumor tissues. PPAR-gamma was found to be overexpressed as a result of 1500 ppm nimesulide treatment and was not detected in tumors from control or 250-1000 ppm nimesulide-treated mice. Nimesulide (1500 ppm) significantly reduced intratumor PGE(2) levels (P < 0.001) and induced apoptosis in 25% of tumor cells as compared with control tumors.
Nimesulide (1500 ppm) induced growth inhibition of A549 lung tumors is associated with the reduction of intratumor PGE(2) levels but without affecting the expression of COX-2. Nimesulide-induced enhancement of the expression of PPAR-gamma may also contribute to its antitumor effect, which needs to be further investigated.
本研究的目的是评估环氧化酶（COX）-2抑制剂尼美舒利对人肺A549腺癌皮下肿瘤生长抑制的作用，并评估尼美舒利对从小鼠收获的肺肿瘤中COX-2和过氧化物酶体增殖物激活受体（PPAR）-γ表达的影响。
将雌性裸鼠皮下接种A549肺肿瘤，肿瘤植入1天后，给小鼠喂食含250 - 1500 ppm剂量尼美舒利的饲料。每周监测两次肿瘤大小，从小鼠分离的肿瘤样本用于通过酶免疫测定法测定前列腺素E2（PGE2）水平，通过蛋白质印迹法和免疫组织化学法测定COX-2和PPAR-γ的表达。此外，通过末端脱氧核苷酸转移酶介导的缺口末端标记染色法测定肿瘤标本中的细胞凋亡诱导情况。
尼美舒利治疗显示出对A549肿瘤的剂量依赖性生长抑制作用，在1500 ppm尼美舒利时最大抑制率为77.7%。蛋白质印迹实验显示，在对照和尼美舒利（250 - 1500 ppm）治疗的小鼠肿瘤组织中，COX-2的表达相似。发现1500 ppm尼美舒利治疗导致PPAR-γ过度表达，而在对照或250 - 1000 ppm尼美舒利治疗的小鼠肿瘤中未检测到。与对照肿瘤相比，尼美舒利（1500 ppm）显著降低肿瘤内PGE2水平（P < 0.001），并诱导25%的肿瘤细胞凋亡。
尼美舒利（1500 ppm）诱导的A549肺肿瘤生长抑制与肿瘤内PGE2水平降低有关，但不影响COX-2的表达。尼美舒利诱导的PPAR-γ表达增强也可能有助于其抗肿瘤作用，这需要进一步研究。
