PMID- 27144340
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20220321
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 23
DP  - 2016 Jun 7
TI  - Metformin restores crizotinib sensitivity in crizotinib-resistant human lung 
      cancer cells through inhibition of IGF1-R signaling pathway.
PG  - 34442-52
LID - 10.18632/oncotarget.9120 [doi]
AB  - AIM: Despite the impressive efficacy of crizotinib for the treatment of 
      ALK-positive non-small cell lung cancer, patients invariably develop therapeutic 
      resistance. Suppression of the IGF-1R signaling pathway may abrogate this 
      acquired mechanism of drug resistance to crizotinib. Metformin, a widely used 
      antidiabetic agent, may reverse crizotinib resistance through inhibition of 
      IGF-1R signaling. RESULTS: The present study revealed that metformin effectively 
      increased the sensitivity of both crizotinib-sensitive and -resistant non-small 
      cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and 
      invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in 
      crizotinib-resistant cells. Furthermore, the addition of IGF-1 to 
      crizotinib-sensitive H2228 cells induced crizotinib resistance, which was 
      overcome by metformin. EXPERIMENTAL DESIGN: The effects of metformin to reverse 
      crizotinib resistance were examined in vitro by using 
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 
      incorporation assay, flow cytometry analysis, Western blot analysis, and 
      colony-forming assay. CONCLUSIONS: Metformin may be used in combination with 
      crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong 
      survival.
FAU - Li, Li
AU  - Li L
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Wang, Yubo
AU  - Wang Y
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Peng, Tao
AU  - Peng T
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Zhang, Kejun
AU  - Zhang K
AD  - Department of Clinical Labratory, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Lin, Caiyu
AU  - Lin C
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Han, Rui
AU  - Han R
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - Lu, Conghua
AU  - Lu C
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
FAU - He, Yong
AU  - He Y
AD  - Department of Respiratory Disease, Daping Hospital, Third Military Medical 
      University, Chongqing 400042, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents)
RN  - 0 (IGF1R protein, human)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Somatomedin)
RN  - 53AH36668S (Crizotinib)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Anaplastic Lymphoma Kinase
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Crizotinib
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/metabolism
MH  - Metformin/*pharmacology
MH  - Neoplasm Invasiveness/pathology
MH  - Pyrazoles/*pharmacology
MH  - Pyridines/*pharmacology
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Receptor, IGF Type 1
MH  - Receptors, Somatomedin/*antagonists & inhibitors
MH  - Signal Transduction/drug effects
PMC - PMC5085167
OTO - NOTNLM
OT  - IGF-1R
OT  - crizotinib
OT  - lung cancer
OT  - metformin
OT  - resistance
COIS- The authors declare no potential conflicts of interest.
EDAT- 2016/05/05 06:00
MHDA- 2018/01/06 06:00
PMCR- 2016/06/07
CRDT- 2016/05/05 06:00
PHST- 2015/11/01 00:00 [received]
PHST- 2016/03/31 00:00 [accepted]
PHST- 2016/05/05 06:00 [entrez]
PHST- 2016/05/05 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
PHST- 2016/06/07 00:00 [pmc-release]
AID - 9120 [pii]
AID - 10.18632/oncotarget.9120 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Jun 7;7(23):34442-52. doi: 10.18632/oncotarget.9120.