Woo Jong Kyu, Kang Ju-Hee, Jang Yeong-Su, Ro Seonggu, Cho Joong Myung, Kim Hwan-Mook, Lee Sang-Jin, Oh Seung Hyun
College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea.
Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
Oncol Rep. 2015 Apr;33(4):1947-55. doi: 10.3892/or.2015.3793. Epub 2015 Feb 10.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.
非甾体抗炎药（NSAIDs）已被认为是一类潜在的新型抗肿瘤预防或治疗药物。本研究的目的是评估新型NSAID CG100649的抗肿瘤活性。CG100649是一种新型的COX-2和碳酸酐酶（CA）-I/-II双重抑制剂。在本研究中，我们研究了CG100649介导抑制结肠癌生长和发展的替代机制。锚定依赖性和非依赖性克隆形成试验表明，CG100649抑制人结肠癌细胞的克隆形成能力。流式细胞术分析表明，CG100649诱导结肠癌细胞发生G2/M期细胞周期阻滞。动物研究表明，CG100649抑制裸鼠结肠癌异种移植瘤的生长。此外，定量PCR和FACS分析表明，CG100649上调结肠癌细胞中肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体（DR4和DR5）的表达，但降低诱饵受体（DcR1和DcR2）的表达。结果表明，CG100649处理可使TRAIL介导的生长抑制和凋亡性细胞死亡敏感化。联合治疗显著抑制了APCmin/+小鼠肠道息肉的形成。我们的数据清楚地表明，CG100649对结肠癌具有预防和治疗活性。本研究可能有助于确定NSAID CG100649的潜在益处，以实现更好的结肠癌治疗反应。
