PARP inhibitors – theoretical basis and clinical application

Dębska, Sylwia; Kubicka, Joanna; Czyżykowski, Rafał; Habib, Maja; Potemski, Piotr

doi:10.5604/17322693.999033

Cited by 8 publications

(6 citation statements)

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“…The induction of DSBs is lethal to cells with mutated BRCA 1 or 2. The synthetic lethality concept has contributed to the application of PARP inhibitors for the treatment of BRCA1-or 2mutated cancers, which are homologous recombination repair pathway-deficient (42). However, authors have reported acquired resistance to treatment with PARP inhibitors in most patients with advanced cancer, and not all patients who carry BRCA1 or 2 mutations have responses to these inhibitors (43,44).…”

Section: Discussionmentioning

confidence: 99%

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Pradeep

Villar‐Prados

et al. 2019

Molecular Cancer Therapeutics

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EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 AE 0.13 g) than those treated with a vehicle (1.19 AE 1.09 g), EP-100 alone (0.62 AE 0.78 g), or olaparib alone (0.50 AE 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Pradeep

Villar‐Prados

et al. 2019

Molecular Cancer Therapeutics

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“…SATB1 is involved in tumor progression and has been suggested to be an independent prognostic factor [7]. In its role as an important protein in chromatin reorganization, SATB1 can up-regulate expression of PARP1 which takes part in single-stranded DNA repair resulting in synthetic lethality in BRCA1/2 defective cancers.PARP1 inhibitors have been successfully applied in clinical treatment for breast and ovarian cancers [28], [29]. Although BRCA1/2 mutations can incite genomic instability and are strong predictors of breast cancer [30]–[32], SATB1 abnormality is unrelated to BRCA1/2 mutations [7] indicating that SATB1 affects DNA repair in a manner which is independent of BRCA1/2.…”

Section: Discussionmentioning

confidence: 99%

SATB1 Expression Is Associated with Biologic Behavior in Colorectal Carcinoma In Vitro and In Vivo

Zhang

et al. 2013

PLoS ONE

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There is increasing evidence that Special AT-rich sequence-binding protein 1 (SATB1) is aberrantly expressed in several cancers and is correlated with clinicopathologic parameters in these tumors. In this study, we showed over-expression of SATB1 in 80 cases of colorectal cancer and in 3 colorectal cancer cell lines and found expression levels were strongly associated with tumor differentiation and stage. Expression levels of SATB1 protein were higher in poorly-differentiated as compared with well-differentiated cell lines, and both quantity and distribution patterns of SATB1 were associated with tumor differentiation and pTNM stage. Strikingly, we further investigated the effect of down regulation of SATB1 expression on malignant phenotypic features in colorectal cancer cells in vitro, and showed that SABT1 down-regulation negatively affected growth potential, anchorage-independent colony formation and cancer cell invasion, and resulted in increased apoptosis. SATB1 expression was positively associated with the expression of various biological and genetic markers, including Cyclin D1, MMP-2, NF-κB, and PCNA, and was associated with loss of APC and BRAFV600E. These findings suggest that SATB1 is involved in the carcinogenesis, development and progression of colorectal cancer.

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“…The other area of research into PARP inhibitors is related to their synergistic activity with genotoxic cytostatic agents and radiotherapy (16,17).…”

Section: Introductionmentioning

confidence: 99%

Nuclear-cytoplasmic PARP-1 expression as an unfavorable prognostic marker in lymph node-negative early breast cancer: 15-year follow-up

Donizy

Pietrzyk²,

Hałoń

et al. 2014

Oncology Reports

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Abstract. PARP-1 plays an important role in DNA damage repair and maintaining genome integrity by repairing DNA single-strand breaks (SSBs) by base excision repair (BER). The aim of the present study was to examine the expression of PARP-1 in breast cancer (BC) patients and to assess the relationship between the subcellular localization of this protein and clinicopathological characteristics. The reactivity of PARP-1 was analyzed by immunohistochemistry in a homogeneous group of 83 stage II ductal BC patients with a 15-year follow-up. Immunostaining of PARP-1 was also evaluated in 4 human BC cell lines and resistance prediction profile for 11 anticancer agents was performed using 3 models of drug-resistant cell lines. Nuclear-cytoplasmic expression (NCE) was associated with shorter overall survival, which was not statistically significant during the 10-year follow-up but became statistically significant after 10 years of observation, during the 15-year follow-up (P=0.015). Analysis performed in subgroups of patients with (N+) and without (N-) nodal metastases showed that NCE was associated with poor clinical outcome in N-patients (P=0.017). Multivariate analysis confirmed a significant impact of NCE on unfavorable prognosis in N-early BC. The presence of PARP-1 NCE may be a new potential unfavorable prognostic factor in lymph node-negative early BC.

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PARP inhibitors – theoretical basis and clinical application

Cited by 8 publications

References 0 publications

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

SATB1 Expression Is Associated with Biologic Behavior in Colorectal Carcinoma In Vitro and In Vivo

Nuclear-cytoplasmic PARP-1 expression as an unfavorable prognostic marker in lymph node-negative early breast cancer: 15-year follow-up

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