PMID- 29853661
OWN - NLM
STAT- MEDLINE
DCOM- 20190701
LR  - 20221207
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 132
IP  - 13
DP  - 2018 Jul 16
TI  - Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous 
      cell carcinoma is reversed by GW8510 through autophagy induction.
PG  - 1417-1433
LID - 10.1042/CS20180010 [doi]
AB  - Although chemotherapeutic regimen containing gemcitabine is the first-line 
      therapy for advanced lung squamous cell carcinoma (LSCC), gemcitabine resistance 
      remains an important clinical problem. Some studies suggest that overexpressions 
      of ribonucleotide reductase (RNR) subunit M2 (RRM2) may be involved in 
      gemcitabine resistance. We used a novel RRM2 inhibitor, GW8510, as a gemcitabine 
      sensitization agent to investigate the therapeutic utility in reversing 
      gemcitabine resistance in LSCC. Results showed that the expressions of RRM2 were 
      increased in gemcitabine intrinsic resistant LSCC cells upon gemcitabine 
      treatment. GW8510 not only suppressed LSCC cell survival, but also sensitized 
      gemcitabine-resistant cells to gemcitabine through autophagy induction mediated 
      by RRM2 down-regulation along with decrease in dNTP levels. The combination of 
      GW8510 and gemcitabine produced a synergistic effect on killing LSCC cells. The 
      synergism of the two agents was impeded by addition of autophagy inhibitors 
      chloroquine (CQ) or bafilomycin A1 (Baf A1), or knockdown of the autophagy gene, 
      Bcl-2-interacting protein 1 (BECN1). Moreover, GW8510-caused LSCC cell 
      sensitization to gemcitabine through autophagy induction was parallel with 
      impairment of DNA double-strand break (DSB) repair and marked increase in cell 
      apoptosis, revealing a cross-talk between autophagy and DNA damage repair, and an 
      interplay between autophagy and apoptosis. Finally, gemcitabine sensitization 
      mediated by autophagy induction through GW8510-caused RRM2 down-regulation was 
      demonstrated in vivo in gemcitabine-resistant LSCC tumor xenograft, further 
      indicating that the sensitization is dependent on autophagy activation. In 
      conclusion, GW8510 can reverse gemcitabine resistance in LSCC cells through RRM2 
      downregulation-mediated autophagy induction, and GW850 may be a promising 
      therapeutic agent against LSCC as it combined with gemcitabine.
CI  - (c) 2018 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Chen, Ping
AU  - Chen P
AD  - Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China.
FAU - Wu, Jian-Nong
AU  - Wu JN
AD  - Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 
      China.
FAU - Shu, Yang
AU  - Shu Y
AD  - Center of Medical Experiment, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China.
FAU - Jiang, He-Guo
AU  - Jiang HG
AD  - Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China.
FAU - Zhao, Xiao-Hui
AU  - Zhao XH
AD  - Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 
      China.
FAU - Qian, Hai
AU  - Qian H
AD  - Institute of Medical Science, Jiangsu University, Zhenjiang, China.
FAU - Chen, Kang
AU  - Chen K
AD  - Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China.
FAU - Lan, Ting
AU  - Lan T
AD  - Institute of Medical Science, Jiangsu University, Zhenjiang, China.
FAU - Chen, Chen-Guo
AU  - Chen CG
AD  - Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China.
FAU - Li, Jian
AU  - Li J
AD  - Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 
      Zhenjiang, China lijian541226@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180709
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (GW8510)
RN  - 0 (Indoles)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 1.17.4.- (ribonucleotide reductase M2)
RN  - EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Autophagy/*drug effects
MH  - Carcinoma, Squamous Cell/*drug therapy/enzymology/pathology
MH  - Deoxycytidine/*analogs & derivatives/pharmacology
MH  - Down-Regulation/drug effects
MH  - Drug Resistance, Neoplasm/drug effects/physiology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Heterografts
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Lung Neoplasms/*drug therapy/enzymology/pathology
MH  - Male
MH  - Mice, Inbred NOD
MH  - Ribonucleoside Diphosphate Reductase/*antagonists & inhibitors/physiology
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
MH  - Gemcitabine
OTO - NOTNLM
OT  - Autophagy induction
OT  - GW8510
OT  - Gemcitabine
OT  - Lung squamous cell carcinoma
OT  - RRM2
OT  - Resistance
EDAT- 2018/06/02 06:00
MHDA- 2019/07/02 06:00
CRDT- 2018/06/02 06:00
PHST- 2018/01/06 00:00 [received]
PHST- 2018/05/13 00:00 [revised]
PHST- 2018/05/25 00:00 [accepted]
PHST- 2018/06/02 06:00 [pubmed]
PHST- 2019/07/02 06:00 [medline]
PHST- 2018/06/02 06:00 [entrez]
AID - CS20180010 [pii]
AID - 10.1042/CS20180010 [doi]
PST - epublish
SO  - Clin Sci (Lond). 2018 Jul 9;132(13):1417-1433. doi: 10.1042/CS20180010. Print 
      2018 Jul 16.