PMID- 19724920
OWN - NLM
STAT- MEDLINE
DCOM- 20091211
LR  - 20211020
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 35
IP  - 4
DP  - 2009 Oct
TI  - The differential cell signaling effects of two positional isomers of the 
      anticancer NO-donating aspirin.
PG  - 837-44
AB  - We studied the mechanism by which the para and meta positional isomers of nitric 
      oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These 
      compounds are promising chemopreventive agents and represent a broader class of 
      novel drugs. The two isomers differ drastically in their 24-h IC50s for cell 
      growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined 
      their effects on cell signaling cascades, including predominantly the mitogen 
      activated protein kinases (MAPKs). The principal differences between the two 
      isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the 
      predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is 
      on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier 
      effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both 
      isomers seem to have similar effects on AP-1 binding, the main difference between 
      them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is 
      late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's 
      effect occurs later and is weaker; and f) cell cycle changes follow the effect on 
      p21 expression. Our findings underscore the role of positional isomerism in 
      modulating the pharmacological effects of drugs and have potentially important 
      implications for the further development of these chemoprevention agents.
FAU - Hua, Amy
AU  - Hua A
AD  - Division of Cancer Prevention, Department of Medicine, Stony Brook University, 
      Stony Brook, New York 11794-5200, USA.
FAU - Mackenzie, Gerardo G
AU  - Mackenzie GG
FAU - Rigas, Basil
AU  - Rigas B
LA  - eng
GR  - R01 CA101019/CA/NCI NIH HHS/United States
GR  - R01 CA10101902/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (ATF2 protein, human)
RN  - 0 (Activating Transcription Factor 2)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CCND1 protein, human)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Transcription Factor AP-1)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.7.1.24 (Mitogen-Activated Protein Kinase 9)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EH04H13L6B (nitroaspirin)
RN  - R16CO5Y76E (Aspirin)
SB  - IM
MH  - Activating Transcription Factor 2/metabolism
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Aspirin/*analogs & derivatives/chemistry/pharmacology
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Colonic Neoplasms/genetics/*metabolism/pathology
MH  - Cyclin D1/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - HT29 Cells
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Isomerism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Mitogen-Activated Protein Kinase 8/metabolism
MH  - Mitogen-Activated Protein Kinase 9/metabolism
MH  - Nitric Oxide Donors/chemistry/*pharmacology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-jun/metabolism
MH  - RNA Interference
MH  - Signal Transduction/*drug effects/genetics
MH  - Structure-Activity Relationship
MH  - Time Factors
MH  - Transcription Factor AP-1/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC3565755
MID - NIHMS435720
EDAT- 2009/09/03 06:00
MHDA- 2009/12/16 06:00
PMCR- 2013/02/06
CRDT- 2009/09/03 09:00
PHST- 2009/09/03 09:00 [entrez]
PHST- 2009/09/03 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2013/02/06 00:00 [pmc-release]
AID - 10.3892/ijo_00000397 [doi]
PST - ppublish
SO  - Int J Oncol. 2009 Oct;35(4):837-44. doi: 10.3892/ijo_00000397.