PMID- 26760500
OWN - NLM
STAT- MEDLINE
DCOM- 20160708
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 1
DP  - 2016
TI  - Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived 
      Xenografts.
PG  - e0147113
LID - 10.1371/journal.pone.0147113 [doi]
LID - e0147113
AB  - There is currently tremendous interest in developing anti-cancer therapeutics 
      targeting cell signaling pathways important for both cancer cell metabolism and 
      growth. Several epidemiological studies have shown that diabetic patients taking 
      metformin have a decreased incidence of pancreatic cancer. This has prompted 
      efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic 
      modality in pancreatic cancer. Preclinical studies in cell line xenografts and 
      one study in patient-derived xenograft (PDX) models were promising, while 
      recently published clinical trials showed no benefit to adding metformin to 
      combination therapy regimens for locally advanced and metastatic pancreatic 
      cancer. PDX models in which patient tumors are directly engrafted into 
      immunocompromised mice have been shown to be excellent preclinical models for 
      biomarker discovery and therapeutic development. We evaluated the response of 
      four PDX tumor lines to metformin treatment and found that all four of our PDX 
      lines were resistant to metformin. We found that the mechanisms of resistance may 
      occur through lack of sustained activation of adenosine monophosphate-activated 
      protein kinase (AMPK) or downstream reactivation of the mammalian target of 
      rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors 
      failed to improve responses in cell lines, which further indicates that metformin 
      alone or in combination with mTOR inhibitors will be ineffective in patients, and 
      that resistance to metformin may occur through multiple pathways. Further studies 
      are required to better understand these mechanisms of resistance and inform 
      potential combination therapies with metformin and existing or novel 
      therapeutics.
FAU - Lipner, Matthew B
AU  - Lipner MB
AD  - Department of Pharmacology, School of Medicine, The University of North Carolina, 
      Chapel Hill, NC, United States of America.
AD  - Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel 
      Hill, NC, United States of America.
FAU - Marayati, Raoud
AU  - Marayati R
AD  - Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel 
      Hill, NC, United States of America.
FAU - Deng, Yangmei
AU  - Deng Y
AD  - Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel 
      Hill, NC, United States of America.
FAU - Wang, Xianxi
AU  - Wang X
AD  - Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel 
      Hill, NC, United States of America.
FAU - Raftery, Laura
AU  - Raftery L
AD  - ProHealth Care Regional Cancer Center, Waukesha, WI, United States of America.
FAU - O'Neil, Bert H
AU  - O'Neil BH
AD  - Department of Medicine, Division of Medical Oncology, University of Indiana, 
      Indianapolis, IN, United States of America.
FAU - Yeh, Jen Jen
AU  - Yeh JJ
AD  - Department of Pharmacology, School of Medicine, The University of North Carolina, 
      Chapel Hill, NC, United States of America.
AD  - Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel 
      Hill, NC, United States of America.
AD  - Department of Surgery, Division of Surgical Oncology and Endocrinology, The 
      University of North Carolina, Chapel Hill, NC, United States of America.
LA  - eng
GR  - P30 ES010126/ES/NIEHS NIH HHS/United States
GR  - R01 CA193650/CA/NCI NIH HHS/United States
GR  - R01 CA140424/CA/NCI NIH HHS/United States
GR  - T32 GM007040/GM/NIGMS NIH HHS/United States
GR  - CA140424/CA/NCI NIH HHS/United States
GR  - CA193650/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160113
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Drug Synergism
MH  - Gene Expression
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Pancreatic Neoplasms/drug therapy/metabolism/*pathology
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
MH  - Tumor Burden
MH  - Xenograft Model Antitumor Assays
PMC - PMC4711922
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/01/14 06:00
MHDA- 2016/07/09 06:00
PMCR- 2016/01/13
CRDT- 2016/01/14 06:00
PHST- 2014/07/25 00:00 [received]
PHST- 2015/12/29 00:00 [accepted]
PHST- 2016/01/14 06:00 [entrez]
PHST- 2016/01/14 06:00 [pubmed]
PHST- 2016/07/09 06:00 [medline]
PHST- 2016/01/13 00:00 [pmc-release]
AID - PONE-D-14-33493 [pii]
AID - 10.1371/journal.pone.0147113 [doi]
PST - epublish
SO  - PLoS One. 2016 Jan 13;11(1):e0147113. doi: 10.1371/journal.pone.0147113. 
      eCollection 2016.