Ding Ning, Cui Xiao-Xing, Gao Zhi, Huang Huarong, Wei Xingchuan, Du Zhiyun, Lin Yong, Shih Weichung Joe, Rabson Arnold B, Conney Allan H, Hu Chunhong, Zheng Xi
Second Xiangya Hospital, Central South University, Changsha 410011, P.R. China.
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Int J Oncol. 2014 Jun;44(6):2139-45. doi: 10.3892/ijo.2014.2350. Epub 2014 Mar 19.
Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
由于K-Ras突变和环氧合酶-2（COX-2）过表达是大多数胰腺癌患者的特征，因此应考虑采用同时给予抑制这两个靶点功能的药物来抑制胰腺癌进展和生长的方法。在本研究中，我们评估了阿托伐他汀（立普妥）、塞来昔布（西乐葆）和替匹法尼（Zarnestra）对人胰腺癌生长的影响。在体外研究中，我们发现用阿托伐他汀、塞来昔布和替匹法尼联合处理人胰腺肿瘤细胞，比单独使用每种药物或任意两种药物组合，对生长具有更强的抑制作用，对细胞凋亡具有更强的刺激作用。我们还发现，用这三种药物联合处理Panc-1细胞可显著降低磷酸化Erk1/2和Akt的水平。在严重联合免疫缺陷（SCID）小鼠异种移植瘤动物模型中，我们发现每天腹腔注射阿托伐他汀、塞来昔布和替匹法尼的组合，比单独使用每种药物或任意两种药物组合，对小鼠肿瘤生长具有更强的抑制作用。我们的研究结果表明，阿托伐他汀、塞来昔布和替匹法尼联合使用可能是治疗胰腺癌的有效策略。
