Document Detail

Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) activity in PARP-1 silenced tumour cells increases chemosensitivity to temozolomide and to a N3-adenine selective methylating agent.
MedLine Citation:
PMID:  20464779     Owner:  NLM     Status:  MEDLINE    
We recently demonstrated that poly(ADP-ribose) polymerase (PARP)-1 is involved in angiogenesis and tumour aggressiveness. In this study we have compared the influence of abrogation of PARP-1 expression by stable gene silencing to that of the pharmacological inhibition of cellular PARP activity using PARP-1/-2 inhibitors on the chemosensitivity of tumour cells to the wide spectrum methylating agent temozolomide (TMZ) and to the N3-adenine selective methylating agent {1-methyl-4-[1-methyl-4-(3-methoxysulfonylpropanamido)pyrrole-2-carboxamido]-pyrrole-2-carboxamido}propane (Me-Lex). Silencing of PARP-1 in melanoma or cervical carcinoma lines enhanced in vitro sensitivity to TMZ and Me- Lex, and induced a higher level of cell accumulation at the G2/M phase of cell cycle with respect to controls. GPI 15427, which inhibits both PARP-1 and PARP-2, increased sensitivity to TMZ and Me-Lex both in PARP-1-proficient and - deficient cells. However, it induced different cell cycle modulations depending on PARP-1 expression, provoking a G2/M arrest only in PARP-1 silenced cells. Treatment of PARP-1 silenced cells with TMZ or Me-Lex resulted in a more extensive phosphorylation of Chk-1 and p53 as compared to PARP-1 proficient cells. The combination of the methylating agents with GPI 15427 increased Chk-1 and p53 phosphorylation both in PARP-1 proficient or deficient cells. When mice challenged with PARP-1 silenced melanoma cells were treated with the TMZ and PARP inhibitor combination there was an additional reduction in tumour growth with respect to treatment with TMZ alone. These results suggest the involvement of PARP-2 or other PARPs, in the repair of DNA damage provoked by methylating agents, highlighting the importance of targeting both PARP-1 and PARP-2 for cancer therapy.
L Tentori; A Muzi; A S Dorio; M Scarsella; C Leonetti; G M Shah; W Xu; E Camaioni; B Gold; R Pellicciari; F Dantzer; J Zhang; G Graziani
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Current cancer drug targets     Volume:  10     ISSN:  1873-5576     ISO Abbreviation:  Curr Cancer Drug Targets     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-12     Completed Date:  2010-08-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101094211     Medline TA:  Curr Cancer Drug Targets     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  368-83     Citation Subset:  IM    
Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Blotting, Western
Cell Division / drug effects
Cell Line, Tumor
Dacarbazine / analogs & derivatives*,  pharmacology
Drug Synergism
Enzyme Inhibitors / pharmacology*
Flow Cytometry
G2 Phase / drug effects
Hela Cells
Melanoma, Experimental / pathology
Netropsin / analogs & derivatives*,  pharmacology
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*,  genetics
Grant Support
MOP-89964//Canadian Institutes of Health Research; R01 CA29008/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/methyl lexitropsin; 1438-30-8/Netropsin; 4342-03-4/Dacarbazine; 85622-93-1/temozolomide; EC Polymerases

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