Anti-tumor effect of bisphosphonate (YM529) on non-small cell lung cancer cell lines.
BACKGROUND
YM529 is a newly developed nitrogen-containing bisphosphonate (BP) classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC).


METHODS
Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157) were measured by MTS assay and calculated inhibition concentration 50 % (IC50) values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method). We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis.


RESULTS
We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 microM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819).


CONCLUSIONS
Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.
Koshimune
Ryuichiro
R
Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama city, Okayama 700-8558, Japan. koshiryu16@hotmail.com <koshiryu16@hotmail.com>
Aoe
Motoi
M
Toyooka
Shinichi
S
Hara
Fumikata
F
Ouchida
Mamoru
M
Tokumo
Masaki
M
Sano
Yoshifumi
Y
Date
Hiroshi
H
Shimizu
Nobuyoshi
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; C087958:YM 529