Pharmacological Modulation of Poly(ADP-ribose) Polymerase-Mediated Cell Death: Exploitation in Cancer Chemotherapy

Nguewa, Paul A.; Fuertes, Miguel A.; Alonso, Carlos; Pérez, Jose

doi:10.1124/mol.64.5.1007

Cited by 37 publications

(30 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mol Cancer Ther 2007;6 (8). August 2007 at Â100 magnification; counts were normalized to background (0.1% DMSO).…”

Section: Molecular Cancer Therapeutics 2293mentioning

confidence: 99%

“…PARP-1 is activated by, and implicated in, base excision repair of DNA strand breaks caused by ionizing radiation, or following enzymatic repair of DNA lesions induced by methylating agents, topoisomerase I inhibitors, and other chemotherapeutic agents, such as cisplatin and bleomycin (5,6). The role of PARP activation in cell survival and repair following sublethal DNA damage coupled with data showing an inverse correlation of PARP-1 activity with the degree of tumor cell differentiation makes PARP-1 a viable target for modulating the responsiveness of tumor cells to cytotoxic therapies (7,8). In support of this hypothesis, studies have shown the ability of PARP-1 inhibitors to increase the in vitro and in vivo antitumor effects of radiation or chemotherapy and/or restore sensitivity to temozolomide in temozolomide-resistant tumor cells (1,9,10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

Miknyoczki¹,

Chang²,

Grobelny³

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide-and camptothecin-induced cytotoxicity, DNA damage, and G 2 -M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/ or lengthened duration of time tumor cells accumulated in chemotherapy-induced G 2 -M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed ''stand alone'' antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose-and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors. [Mol Cancer Ther 2007;6(8):2290-302]

show abstract

“…Mol Cancer Ther 2007;6 (8). August 2007 at Â100 magnification; counts were normalized to background (0.1% DMSO).…”

Section: Molecular Cancer Therapeutics 2293mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

Miknyoczki¹,

Chang²,

Grobelny³

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…However, in the case of extensive DNA damage, PARP-1 overactivation induces a decrease of NAD þ and ATP levels, leading to cell death. The type of cell death seems to be dictated by the amplitude of PARP-1-induced decrease of ATP levels (Nguewa et al, 2003). Apoptosis, which is an energy-requiring process, occurs when ATP loss is limited.…”

Section: Discussionmentioning

confidence: 99%

“…PARP-1 participates in the death signal triggered by a co-treatment with TNFa and ATRA Besides its essential role in DNA repair, the nuclear enzyme PARP-1 can promote mitochondrial cell death (Boulares et al, 2001;Yu et al, 2002;Nguewa et al, 2003). We investigated the potential role of PARP-1 in cell death triggered by the combination of TNFa and ATRA.…”

Section: Atra Amplifies the Apoptotic Signal Triggered By Tnfamentioning

confidence: 99%

A PARP-1/JNK1 cascade participates in the synergistic apoptotic effect of TNFα and all-trans retinoic acid in APL cells

et al. 2007

View full text Add to dashboard Cite

When administrated by isolated limb perfusion, tumor necrosis factor a (TNFa) is an efficient antitumor agent that improves drug penetration and destroys angiogenic vessels. Moreover, the pronounced potentiation of TNFainduced apoptosis by NF-jB inhibitors suggest that these compounds could enhance TNFa antitumor efficacy through direct induction of tumor cell apoptosis. Therefore, attempts at amplifying signaling pathways that mediate TNFa antitumor effects could help to design combination therapies improving its efficiency. We report that nanomolar concentrations of all-trans retinoic acid (ATRA) amplify TNFa-induced apoptosis in APL cells expressing a specific repressor of NF-jB activation. This effect is abolished by the pan-caspase inhibitor, Z-VADfmk and by caspase-8 and -9 inhibitors. Cell death is accompanied by a drop of mitochondrial potential and by poly (ADP-ribose) polymerase (PARP) activation. Using specific PARP-1 inhibitors and siRNAs, we show that PARP-1 is essential for the synergistic apoptotic effect and c-Jun N-terminal kinase 1 (JNK1) activation triggered by the ATRA/TNFa combination. JNK1 siRNAs reduce ATRA/TNFa-induced apoptosis, mitochondrial release of cytochrome c and caspase-9 activation. Altogether, these results identify a novel mechanism of PARP-1-induced apoptosis, in which JNK1 provides a link between PARP-1 activation and mitochondrial pathway of caspase-9 activation. This study also suggests that inclusion of nanomolar doses of ATRA could be clinically beneficial in amplifying TNFa-induced antitumor signals.

show abstract

“…They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects (Papeo et al, 2013). In tumor cells sensitive or moderately sensitive to chemotherapy, a low or moderate dose of drug in combination with PARP inhibition may result in efficient block of DNA repair and subsequent apoptotic cell death (Nguewa et al, 2003).…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Endpoint of Cancer Treatment: Targeted Therapies

Topçul

Çeti̇n²

2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Nowadays there are several limitations in cancer treatment. One of these is the use of conventional medicines which not only target cancer cells and thus also cause high toxicity precluding effective treatment. Recent elucidation of mechanisms that cause cancer has led to discovery of novel key molecules and pathways which have have become successful targets for the treatments that eliminate only cancer cells. These so-called targeted therapies offer new hope for millions of cancer patients, as briefly reveiwed here focusing on different types of agents, like PARP, CDK, tyrosine kinase, farnysyl transferase and proteasome inhibitors, monoclonal antibodies and antiangiogenic agents.

show abstract

Pharmacological Modulation of Poly(ADP-ribose) Polymerase-Mediated Cell Death: Exploitation in Cancer Chemotherapy

Cited by 37 publications

References 71 publications

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

A PARP-1/JNK1 cascade participates in the synergistic apoptotic effect of TNFα and all-trans retinoic acid in APL cells

Endpoint of Cancer Treatment: Targeted Therapies

Contact Info

Product

Resources

About