PMID- 31027492
OWN - NLM
STAT- MEDLINE
DCOM- 20190904
LR  - 20220410
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 38
IP  - 1
DP  - 2019 Apr 26
TI  - Activity and molecular targets of pioglitazone via blockade of proliferation, 
      invasiveness and bioenergetics in human NSCLC.
PG  - 178
LID - 10.1186/s13046-019-1176-1 [doi]
LID - 178
AB  - BACKGROUND: Pioglitazone, a synthetic peroxisome proliferator activated receptor 
      (PPAR-gamma) ligand, is known as an antidiabetic drug included in the 
      thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell 
      metabolism and recently a role in the inhibition of numerous cancer cell 
      processes has been described. METHODS: In our work we investigate the anti-tumor 
      effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) 
      and also, we generated ex-vivo three-dimensional (3D) cultures from human lung 
      adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The 
      inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell 
      invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. 
      RESULTS: Pioglitazone reduced proliferative and invasive abilities with an IC(50) 
      ranging between 5 and 10 muM and induced apoptosis of NSCLC cells. mRNA microarray 
      expression profiling showed a down regulation of MAPK, Myc and Ras genes after 
      treatment with pioglitazone; altered gene expression was confirmed by protein 
      analysis in a dose-related reduction of survivin and phosphorylated proteins 
      levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that 
      pioglitazone affects TGFbeta pathway, which is important in the 
      epithelial-to-mesenchimal transition (EMT) process, by down-regulating TGFbetaR1 and 
      SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a 
      proportional reduction of markers of altered glucose metabolism in treated cells 
      demonstrated also cell bioenergetics modulation by pioglitazone. CONCLUSIONS: 
      Data indicate that PPAR-gamma agonists represent an attractive treatment tool and by 
      suppression of cell growth (in vitro and ex vivo models) and of invasion via 
      blockade of MAPK cascade and TGFbeta/SMADs signaling, respectively, and its role in 
      cancer bioenergetics and metabolism indicate that PPAR-gamma agonists represent an 
      attractive treatment tool for NSCLC.
FAU - Ciaramella, Vincenza
AU  - Ciaramella V
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Sasso, Ferdinando Carlo
AU  - Sasso FC
AD  - Department of Medicine, Surgery, Neurology, Metabolism and Geriatrics School of 
      Medicine and Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
FAU - Di Liello, Raimondo
AU  - Di Liello R
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Corte, Carminia Maria Della
AU  - Corte CMD
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Barra, Giusi
AU  - Barra G
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Viscardi, Giuseppe
AU  - Viscardi G
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Esposito, Giovanna
AU  - Esposito G
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Sparano, Francesca
AU  - Sparano F
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Troiani, Teresa
AU  - Troiani T
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Martinelli, Erika
AU  - Martinelli E
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Orditura, Michele
AU  - Orditura M
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - De Vita, Ferdinando
AU  - De Vita F
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Ciardiello, Fortunato
AU  - Ciardiello F
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy.
FAU - Morgillo, Floriana
AU  - Morgillo F
AD  - Medical Oncology, Department of Precision Medicine, University of Campania "Luigi 
      Vanvitelli", Via Pansini 5, 80138, Naples, Italy. 
      floriana.morgillo@unicampania.it.
LA  - eng
PT  - Journal Article
DEP - 20190426
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (PPAR gamma)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad3 Protein)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
RN  - EC 2.7.11.30 (TGFBR1 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - A549 Cells
MH  - Adenocarcinoma of Lung/*drug therapy/genetics/metabolism/pathology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Glucose/metabolism
MH  - Humans
MH  - Mitogen-Activated Protein Kinase Kinases/genetics
MH  - Neoplasm Invasiveness/genetics/pathology
MH  - PPAR gamma/agonists/*genetics
MH  - Pioglitazone/pharmacology
MH  - Receptor, Transforming Growth Factor-beta Type I/*genetics
MH  - Signal Transduction/genetics
MH  - Smad3 Protein/*genetics
MH  - Transforming Growth Factor beta1/genetics
PMC - PMC6485164
OTO - NOTNLM
OT  - Bioenergetics
OT  - EMT
OT  - Glitazones
OT  - Lung cancer
OT  - Metabolism
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not applicable. CONSENT FOR 
      PUBLICATION: Not applicable. COMPETING INTERESTS: Fortunato Ciardiello: Advisory 
      Boards: Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, 
      Lilly; Institutional Research Grants: Bayer, Roche, Merck, Amgen, AstraZeneca, 
      Ipsen. FlorianaMorgillo: Advisory Boards MSD, Lilly; Institutional Research 
      Grants: AstraZeneca. Ferdinando De Vita: Advisory Board: Lilly, Celgene, Roche, 
      Amgen. Michele Orditura: Advisory Board: Roche, Epionpharma-Italfarmaco, Eisai. 
      All other coauthors have no conflicts of interest to declare for the following 
      manuscript. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to 
      jurisdictional claims in published maps and institutional affiliations.
EDAT- 2019/04/28 06:00
MHDA- 2019/09/05 06:00
PMCR- 2019/04/26
CRDT- 2019/04/28 06:00
PHST- 2019/01/11 00:00 [received]
PHST- 2019/04/14 00:00 [accepted]
PHST- 2019/04/28 06:00 [entrez]
PHST- 2019/04/28 06:00 [pubmed]
PHST- 2019/09/05 06:00 [medline]
PHST- 2019/04/26 00:00 [pmc-release]
AID - 10.1186/s13046-019-1176-1 [pii]
AID - 1176 [pii]
AID - 10.1186/s13046-019-1176-1 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2019 Apr 26;38(1):178. doi: 10.1186/s13046-019-1176-1.