Inhibition of poly(ADP‐ribose) polymerase prevents irinotecan‐induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma

Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; Muzi, Alessia; Mazzon, Emanuela; Vergati, Matteo; Forini, Olindo; Lapidus, Rena G.; Xu, Weizheng; Dorio, Annalisa Susanna; Zhang, Jie; Cuzzocrea, Salvatore; Graziani, Grazia

doi:10.1096/fj.06-5916fje

Cited by 96 publications

(60 citation statements)

References 39 publications

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“…Furthermore, our results show that there is no statistically significant positive correlation between PARP-1 expression and PARP-1 activity in the panel overall ( Figure 3A) or when comparing cells from the same tissue of origin, e.g., the five neuroblastoma cell lines ( Figure 3B). This contrasts to earlier data showing correlation of PARP activity with PARP-1 protein expression in five colon cancer cell lines (Tentori et al, 2006). The lower than expected activity in cells with high levels of expression (e.g., ML-1) could not be explained by the T2444C SNP and indeed the cells with the variant allele did not appear to have lower activity than expected on the basis of expression (Table 1).…”

Section: Discussioncontrasting

confidence: 97%

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

et al. 2009

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BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. METHODS: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. RESULTS: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV ¼ 103%), with the lowest and the highest activity being 2460 pmol PAR/10 6 (HS-5 cells) and 85 750 pmol PAR/10 6 (NGP cells). Lower variation (CV ¼ 32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng mg À1 (HS-5 cells) and the highest being 7.1 ng mg À1 (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. CONCLUSIONS: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA.

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Section: Discussioncontrasting

confidence: 97%

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

et al. 2009

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“…PARP is involved in the recognition and repair of RHPS4-induced telomere damage We next evaluated the consequences of PARP inhibition in RHPS4-treated cells by using both PARP1-specific interference RNA and GPI 15427 (GPI), a wellestablished PARP inhibitor already characterized by our group and the analog (GPI 21016) of which is now in clinical trial (Tentori et al, 2006;Ratnam and Low, 2007). The deconvolution analysis, used to examine the formation of telomere dysfunction induced foci, revealed that either siPARP1 or GPI alone did not induce damage (Figures 3a-c).…”

Section: Parp Inhibition Increases the Efficacy Of Telomere-based Thementioning

confidence: 99%

“…Finally, in the attempt to search for more effective anticancer therapy, we tested whether adding the TOPOI inhibitor could increase the therapeutic efficacy of the GPI/RHPS4 combination. This multi-component therapeutic strategy is based on previous data showing synergistic interaction between RHPS4 and CPT as well as CPT and PARP inhibitors (Tentori et al, 2006;Leonetti et al, 2008), and on data reported in this paper describing the activation of PARP at telomeres upon CPT treatment. The pre-treatment with GPI increased the tumor weight inhibition elicited by either RHPS4 or irinotecan (Figure 5a, left panel and Table 1).…”

Section: Parp Inhibition Increases the Antitumoral Activity Of Rhps4-mentioning

confidence: 99%

“…Treatments were as follows: RHPS4 was given intravenously at 10 mg/kg/ day for 15 consecutive days; irinotecan was administered intraperitoneally at 15 mg/kg/day for 5 consecutive days; GPI 15427 was administered per os at 40 mg/kg/day. In the combination experiments, GPI 15427 was given 1 h before each RHPS4 or irinotecan administration (Tentori et al, 2006;Leonetti et al, 2008). To evaluate antitumor efficacy of the different treatments, HT29 or HCT116 cells were implanted at 3 Â 10 6 cells/mouse and drugs were injected when a tumor mass of approximately 300 or 500 mg was evident in the mice.…”

Section: Analysis Of Parp Activitymentioning

confidence: 99%

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PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

108

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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“…The combinational treatment of PARP inhibitor and topoisomerase I inhibitor has been considered as a potent strategy for cancer therapeutics, especially for colorectal cancer cells (24)(25)(26)(27)(28)(29)(30). However, the mechanisms of inducing topoisomerase I inhibitor hypersensitivity using PARP inhibitor remain unclear and the correlation of the MMR status with the sensitivity to topoisomerase I inhibitor treatment in combination with PARP inhibitor has not been elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

Tahara

Inoue

Sato

et al. 2014

Molecular Cancer Therapeutics

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Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)-deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC 50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase-specific doublestrand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage-reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy.

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Inhibition of poly(ADP‐ribose) polymerase prevents irinotecan‐induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma

Cited by 96 publications

References 39 publications

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

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