Synergy of gemcitabine and lidamycin associated with NF-κB downregulation in pancreatic carcinoma cells

被引:10
作者
Chen, Jing [1 ,2 ,3 ]
Wu, Shu-ying [1 ,2 ]
Ou-Yang, Zhi-gang [1 ,2 ]
Zhen, Yong-su [1 ,2 ]
机构
[1] Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China
[2] Peking Union Med Coll, Beijing 100050, Peoples R China
[3] N China Coal Med Coll, Tangshan 063000, Peoples R China
关键词
lidamycin; gemcitabine; pancreatic cancer; K-ras; NF-kappa B; drug therapy; combination;
D O I
10.1111/j.1745-7254.2008.00774.x
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Aim: To investigate the effects on human pancreatic cancer PANC-1 and SW1990 cells using a combination of lidamycin (LDM) and gemcitabine. Methods: A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the growth inhibition of drugs in PANC-1 and SW1990 cells. The effects on apoptosis were measured by terminal uridine deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry combined with fluorescein-isothiocyanate-Annexin V/propidium iodide staining. The activity of caspase-3 was measured with a special assay kit. The mitochondrial membrane potential was determined by confocal microscopy analyses. The level of mRNA encoding K-ras in the cells was determined by RT-PCR analysis. The expression of K-ras, NF-kappa B, and Bcl-2 was detected by Western blotting analysis. Results: There was a significant reduction in proliferation in the pancreatic cancer cell lines treated with a combination of gemcitabine and LDM. The overall growth inhibition directly correlated with apoptotic cell death. LDM potentiated the gemcitabine-induced cell killing by reducing mitochondrial membrane potential and increasing the caspase-3 activity. Notably, the K-ras mRNA level was significantly reduced with the combination of gemcitabine and LDM. The results for K-ras, NF-kappa B, and Bcl-2 proteins also showed downregulation in the combination group relative to the single-agent treatment and the untreated control. Conclusion: LDM can potentiate the growth inhibition induced by gemcitabine in human pancreatic cancer cells, and the synergy may be associated with NF-kappa B downregulation.
引用
收藏
页码:614 / 619
页数:6
相关论文
共 21 条
[1]   New applications of gemcitabine and future directions in the management of pancreatic cancer [J].
Abbruzzese, JL .
CANCER, 2002, 95 (04) :941-945
[2]   MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES [J].
ALMOGUERA, C ;
SHIBATA, D ;
FORRESTER, K ;
MARTIN, J ;
ARNHEIM, N ;
PERUCHO, M .
CELL, 1988, 53 (04) :549-554
[3]   Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death [J].
Arlt, A ;
Gehrz, A ;
Müerköster, S ;
Vorndamm, J ;
Kruse, ML ;
Fölsch, UR ;
Schäfer, H .
ONCOGENE, 2003, 22 (21) :3243-3251
[4]  
Chen J, 2007, ONCOL REP, V17, P1445
[5]   BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis [J].
Cheng, EHYA ;
Wei, MC ;
Weiler, S ;
Flavell, RA ;
Mak, TW ;
Lindsten, T ;
Korsmeyer, SJ .
MOLECULAR CELL, 2001, 8 (03) :705-711
[6]   Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM, ATR, and DNA-PK kinases [J].
Dziegielewski, J ;
Beerman, TA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (23) :20549-20554
[7]   Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration [J].
Foster, Kelley A. ;
Galeffi, Francesca ;
Gerich, Florian J. ;
Turner, Dennis A. ;
Mueller, Michael .
PROGRESS IN NEUROBIOLOGY, 2006, 79 (03) :136-171
[8]   A NEW MACROMOLECULAR ANTITUMOR ANTIBIOTIC, C-1027 .1. DISCOVERY, TAXONOMY OF PRODUCING ORGANISM, FERMENTATION AND BIOLOGICAL-ACTIVITY [J].
HU, J ;
XUE, YC ;
XIE, MY ;
ZHANG, R ;
OTANI, T ;
MINAMI, Y ;
YAMADA, Y ;
MARUNAKA, T .
JOURNAL OF ANTIBIOTICS, 1988, 41 (11) :1575-1579
[9]   Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule [J].
Huang, Yun-Hong ;
Shang, Bo-Yang ;
Zhen, Yong-Su .
WORLD JOURNAL OF GASTROENTEROLOGY, 2005, 11 (26) :3980-3984
[10]   Cancer statistics, 2006 [J].
Jemal, A ;
Siegel, R ;
Ward, E ;
Murray, T ;
Xu, JQ ;
Smigal, C ;
Thun, MJ .
CA-A CANCER JOURNAL FOR CLINICIANS, 2006, 56 (02) :106-130