摘要
As a novel proteasome inhibitor, remarkable proliferation inhibitory effect of compound YSY-01A was shown on tumor cells in previous studies. However, few studies has reported its effect on gastric cancer and related mechanism. We evaluated the anti-proliferative effect of compound YSY-01A using MGC-803 cells and its anti-tumor effect using xenograft nu-BALB/c mouse model. Cell proliferation inhibition was assessed by SRB assay. Related protein expression levels were determined by Western blot assay. We observed that the compound YSY-01A had a significant proliferation inhibitory effect on MGC-803 cells in vitro. Experiment in vivo showed that the compound YSY-01A had a remarkable growth inhibitory effect on MGC-803 cells xenograft tumor when it was used either alone or in combination with the conventional chemotherapeutic agent 5-fluorouracil （5-FU）. Furthermore, YSY-01A and 5-FU had a synergistic effect on xenograft tumor. Results of molecular experiment showed that the compound YSY-01A had a remarkable inhibitory effect on TNF-c~ and IFN induced NF-KB nuclear translocation. At the same time, the compound YSY-01A could reduce the expression of IKK-~, IL-I~ and iNOS, while it significantly enhanced the expression of COX-2 in MGC-803 ceils. Taken together, compound YSY-01A had an impressive tumor inhibitory effect, and it worked in NF-KB-related pathway, suggesting that the compound YSY-01A was an effective therapeutic drug for patients with gastric cancer. Higher tumor cell growth inhibition after the treatment in a combination with 5-FU indicated that combining YSY-01A with 5-FU might be more effective for displaying tumor cell growth inhibitory effects on gastric cancer cells.
化合物YSY-01A是一种新型蛋白酶体抑制剂,前期研究已初步证实其具有显著的抗肿瘤作用,但是该化合物对人胃癌细胞的作用及相关机制研究尚不明确。本实验旨在评价化合物YSY-01A对人胃癌细胞MGC-803的体外和体内作用,并探讨可能的分子机制。体外研究表明,化合物YSY-01A对人胃癌细胞MGC-803具有显著的增殖抑制作用?体内研究表明,化合物YSY-01A单用及与5-FU联用时均可以显著地抑制裸鼠MGC-803异种移植瘤的生长,并且化合物YSY-01A与5-FU具有协同作用。分子机制研究证实,YSY-01A可以显著地抑制TNF-α和IFN诱导的NF-κB核转位,显著地下调IKK-β、IL-1β、iNOS蛋白的表达和上调COX-2蛋白的表达。综上所述,化合物YSY-01A具有较好的抗肿瘤作用,其机制与NF-κB通路相关蛋白有关。
基金
Eleventh Five-Year Plan for National Science and Technology Major Project(Grant No.2009ZX0930-010)
National Science Foundation of China(Grant No.81172915)
a grant from Major New Drug Research and Development Platform of PekingUniversity(Grant No.2009ZX09301-010)
