PMID- 23179338
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20211021
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 31
IP  - 3
DP  - 2013 Jun
TI  - Characterization of a membrane-active anti-tumor agent, UA8967.
PG  - 576-86
LID - 10.1007/s10637-012-9901-z [doi]
AB  - Deletions or mutations in the tumor suppressor gene DPC4 (deleted in pancreatic 
      carcinoma locus 4) are common in colon and pancreatic cancers. Using the 
      Target-related Affinity Profiling (TRAP) chemical library screening method, a 
      novel agent, UA8967, was selected for further studies because it showed greater 
      potency in DPC4-deleted HCT-116 colon cancer cells. Cytotoxicity studies in six 
      pancreatic cancer cell lines (MiaPaca-2, Panc-1, BxPC3, CF-PAC1, AsPC1, and 
      T3M4), one normal human pancreatic ductal epithelial line (HPDE-6) and the 
      HCT-116 DPC4(+/+) and HCT-116 DPC4(-/-) colon cancer cells showed IC50s ranging 
      from 12-61 muM for exposure times of 72 h. Analysis of schedule dependence showed 
      no advantage for long drug exposure times. There was also no selective inhibition 
      of DNA, RNA or protein synthesis after exposure to UA8967. At 24-48 h, there was 
      an accumulation of cells in G0/G1-phase and a proportionate reduction in S-phase 
      cells. Within 1-6 h of exposure, cells were found to undergo an autophagic 
      response, followed at 24 h by a low level of caspase-independent apoptosis with 
      some necrosis. Because of the relatively non-specific mechanistic effects of 
      UA8967, plasma membrane viability was evaluated using uptake of trypan blue and 
      Sytox(R) Green dyes, and leakage of LDH. There was a dose dependent increase in 
      Sytox(R) Green staining, trypan blue uptake and LDH leakage with increasing 
      concentrations of UA8967, suggesting that UA8967 is affecting the plasma 
      membrane. The DPC4(-/-) cells were more sensitive to UA8967 but not to DMSO, 
      suggesting a drug-specific effect on cell membrane integrity.
FAU - Dorr, Robert T
AU  - Dorr RT
AD  - University of Arizona Cancer Center, 1515 N. Campbell Ave, Rm 4963C, Tucson, AZ 
      85724-5024, USA. bdorr@azcc.arizona.edu
FAU - Samulitis, Betty K
AU  - Samulitis BK
FAU - Wisner, Lee
AU  - Wisner L
FAU - Han, Haiyong
AU  - Han H
FAU - Zhao, Yu
AU  - Zhao Y
FAU - Beroza, Paul
AU  - Beroza P
FAU - Damodaran, Komath
AU  - Damodaran K
FAU - Igarashi, Suzu
AU  - Igarashi S
FAU - Landowski, Terry H
AU  - Landowski TH
FAU - Von Hoff, Daniel D
AU  - Von Hoff DD
LA  - eng
GR  - P01 CA109552/CA/NCI NIH HHS/United States
GR  - P30 CA023074/CA/NCI NIH HHS/United States
GR  - P01-CA109552/CA/NCI NIH HHS/United States
GR  - P30-CA023074/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121123
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (3-((4-benzylpiperazino)methyl)-1H-indole)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - 0 (Piperazines)
RN  - 0 (SMAD4 protein, human)
RN  - 0 (Smad4 Protein)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Cycle/drug effects
MH  - Cell Death/drug effects
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Membrane/drug effects
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Indoles/*pharmacology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Piperazines/*pharmacology
MH  - Smad4 Protein/*genetics
PMC - PMC3624034
MID - NIHMS424226
EDAT- 2012/11/28 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/06/01
CRDT- 2012/11/27 06:00
PHST- 2012/09/17 00:00 [received]
PHST- 2012/11/04 00:00 [accepted]
PHST- 2012/11/27 06:00 [entrez]
PHST- 2012/11/28 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/06/01 00:00 [pmc-release]
AID - 10.1007/s10637-012-9901-z [doi]
PST - ppublish
SO  - Invest New Drugs. 2013 Jun;31(3):576-86. doi: 10.1007/s10637-012-9901-z. Epub 
      2012 Nov 23.