PMID- 22160570
OWN - NLM
STAT- MEDLINE
DCOM- 20120628
LR  - 20211021
IS  - 1573-4978 (Electronic)
IS  - 0301-4851 (Linking)
VI  - 39
IP  - 4
DP  - 2012 Apr
TI  - Synergistic inhibitory effects by the combination of gefitinib and genistein on 
      NSCLC with acquired drug-resistance in vitro and in vivo.
PG  - 4971-9
LID - 10.1007/s11033-011-1293-1 [doi]
AB  - In clinical practice, most patients with non small cell lung cancer (NSCLC) who 
      respond to tyrosine kinase inhibitors eventually progress because of an acquired 
      resistance mutation, T790M, in epidermal growth factor receptor (EGFR). Thus, it 
      is important to identify a new drug to reduce resistance. The aim of this study 
      was to test whether genistein combined with gefitinib is effective against NSCLC 
      in a cell line carrying T790M, and to clarify the underlying mechanisms. The 
      human lung cancer cell line H1975 was used as an in vitro and in vivo model. 
      Cells were treated with gefitinib, genistein, or a combination at a range of 
      concentrations. Cell proliferation was calculated to assess the anticancer 
      effects of the compounds in vitro. Flow cytometry and Western blotting were 
      employed to determine the inhibitory effects on proliferation and the induction 
      of apoptosis. The in vivo effects of the compounds were examined using a 
      xenografted nude mouse model for validation. Gefitinib together with genistein 
      enhanced both growth inhibition and apoptosis; however, the greatest synergistic 
      effect was observed at low concentrations. p-EGFR, p-Akt, and p-mTOR expressions 
      in vitro were reduced more by the combined use of the drugs, whereas caspase-3 
      and PARP activities were increased. Significantly more tumor growth inhibition 
      was detected following combination treatment in the in vivo model. These findings 
      suggest that genistein enhanced the antitumor effects of gefitinib in a NSCLC 
      cell line carrying the T790M mutation. This synergistic activity may be due to 
      increased inhibition of the downstream molecular and pro-apoptotic effects of 
      EGFR.
FAU - Zhu, Hang
AU  - Zhu H
AD  - Department of Child and Adolescent Health, School of Public Health and Tropical 
      Medicine, Southern Medical University, 1023 Southern Shatai Road, Guangzhou, 
      510515, China.
FAU - Cheng, Hua
AU  - Cheng H
FAU - Ren, Yuan
AU  - Ren Y
FAU - Liu, Zhan Guo
AU  - Liu ZG
FAU - Zhang, Yi Fang
AU  - Zhang YF
FAU - De Luo, Bing
AU  - De Luo B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111209
PL  - Netherlands
TA  - Mol Biol Rep
JT  - Molecular biology reports
JID - 0403234
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - DH2M523P0H (Genistein)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic/pathology
MH  - *Drug Resistance, Neoplasm/drug effects
MH  - Drug Synergism
MH  - ErbB Receptors/antagonists & inhibitors/metabolism
MH  - Gefitinib
MH  - Genistein/pharmacology/*therapeutic use
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Lung Neoplasms/*drug therapy/pathology
MH  - Mice
MH  - Mutation/genetics
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - Quinazolines/pharmacology/*therapeutic use
MH  - Signal Transduction/drug effects
MH  - Xenograft Model Antitumor Assays
EDAT- 2011/12/14 06:00
MHDA- 2012/06/29 06:00
CRDT- 2011/12/14 06:00
PHST- 2011/01/26 00:00 [received]
PHST- 2011/11/30 00:00 [accepted]
PHST- 2011/12/14 06:00 [entrez]
PHST- 2011/12/14 06:00 [pubmed]
PHST- 2012/06/29 06:00 [medline]
AID - 10.1007/s11033-011-1293-1 [doi]
PST - ppublish
SO  - Mol Biol Rep. 2012 Apr;39(4):4971-9. doi: 10.1007/s11033-011-1293-1. Epub 2011 
      Dec 9.