PMID- 25749171
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150309
LR  - 20201001
IS  - 1936-5233 (Print)
IS  - 1936-5233 (Electronic)
IS  - 1936-5233 (Linking)
VI  - 8
IP  - 1
DP  - 2015 Feb
TI  - Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma 
      Progression.
PG  - 1-9
LID - S1936-5233(14)00122-3 [pii]
LID - 10.1016/j.tranon.2014.11.001 [doi]
AB  - Our group has previously reported that the majority of human melanomas (>60%) 
      express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate 
      release inhibitor riluzole, a drug currently used to treat amyotrophic lateral 
      sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group 
      previously reported that in vitro riluzole treatment reduces cell growth in 
      three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype 
      phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines 
      harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS 
      mutations) showed only a 35% to 40% decrease in colony formation in soft agar in 
      the presence of riluzole. In this study, we have continued our preclinical 
      studies of riluzole and its effect on melanoma cells alone and in combination 
      with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the 
      mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these 
      combinatorial therapies on various melanoma cell lines in 3D and 2D systems and 
      in vivo. Riluzole combined with mTOR inhibition is more effective at halting 
      melanoma anchorage-independent growth and xenograft tumor progression than either 
      agent alone. PI3K signaling changes associated with this combinatorial treatment 
      shows that 3D (nanoculture) modeling of cell signaling more closely resembles in 
      vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is 
      effective at halting tumor cell progression independent of BRAF mutational 
      status. This makes this combinatorial therapy a potentially viable alternative 
      for metastatic melanoma patients who are BRAF WT and are therefore ineligible for 
      vemurafenib therapy.
CI  - Copyright (c) 2014. Published by Elsevier Inc.
FAU - Rosenberg, Stephen A
AU  - Rosenberg SA
AD  - Department of Human Oncology, University of Wisconsin Hospital and Clinics, 
      Madison, WI, USA; Department of Surgery, Division of Surgical Oncology, Cancer 
      Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New 
      Brunswick, NJ, USA.
FAU - Niglio, Scot A
AU  - Niglio SA
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 
      Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 
      USA.
FAU - Salehomoum, Negar
AU  - Salehomoum N
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Chan, Joseph L-K
AU  - Chan JL
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Jeong, Byeong-Seon
AU  - Jeong BS
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Wen, Yu
AU  - Wen Y
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Li, Jiadong
AU  - Li J
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Fukui, Jami
AU  - Fukui J
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 
      Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 
      USA.
FAU - Chen, Suzie
AU  - Chen S
AD  - Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of 
      Pharmacy, Rutgers University, New Brunswick, NJ, USA.
FAU - Shin, Seung-Shick
AU  - Shin SS
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
FAU - Goydos, James S
AU  - Goydos JS
AD  - Department of Surgery, Division of Surgical Oncology, Cancer Institute of New 
      Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 
      Electronic address: goydosjs@cinj.rutgers.edu.
LA  - eng
GR  - K24 CA138709/CA/NCI NIH HHS/United States
GR  - R01 CA124975/CA/NCI NIH HHS/United States
GR  - R01 CA149627/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Transl Oncol
JT  - Translational oncology
JID - 101472619
PMC - PMC4350641
EDAT- 2015/03/10 06:00
MHDA- 2015/03/10 06:01
PMCR- 2015/03/03
CRDT- 2015/03/10 06:00
PHST- 2014/08/19 00:00 [received]
PHST- 2014/10/30 00:00 [revised]
PHST- 2014/11/03 00:00 [accepted]
PHST- 2015/03/10 06:00 [entrez]
PHST- 2015/03/10 06:00 [pubmed]
PHST- 2015/03/10 06:01 [medline]
PHST- 2015/03/03 00:00 [pmc-release]
AID - S1936-5233(14)00122-3 [pii]
AID - 10.1016/j.tranon.2014.11.001 [doi]
PST - ppublish
SO  - Transl Oncol. 2015 Feb;8(1):1-9. doi: 10.1016/j.tranon.2014.11.001.