Abstract 1314
Background
Cisplatin (CDDP) is used in the treatment of locally advanced disease (FIGO stage IIB-IVA) as well recurrent/metastatic cervical cancer. However toxic side effects and acquired resistance limits its efficacy. Enhanced DNA repair is one of the mechanisms responsible for acquired cisplatin resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating BRCA mutated cancers like breast and ovary cancer, however, little is known about the therapeutic efficacy and mechanism of action of PARP inhibitors in non-BRCA cancer like cervical cancer, either as a single agent or in combination with cisplatin.
Methods
Effect of PARP-1 inhibition (PJ34/PARP-1siRNA) was determined in vitro on cell viability, apoptosis, cell cycle progression, proliferation, invasion and metastasis, clonogenecity and β-catenin signaling in cervical cancer cell lines HeLa and SiHa.
Results
Combination of CDDP with PJ34 or PARP-1 siRNA significantly reduced the cell proliferation and induced cell cycle arrest and apoptosis. Also, a significant decrease in cell survival as well as cell invasion and migration was observed as compared with either CDDP/PJ34 alone. The enhanced CDDP sensitivity by PARP-1 inhibition was determined to be due to inhibition of β-catenin signaling as shown by a decrease in MMP-2 activity, MMP-9, c-myc and cyclin-D1 expression upon treatment with PJ34 and PARP-1 siRNA.
Conclusions
Our data provides experimental evidence on the contribution of PARP-1 inhibition in enhancing the cytotoxicity of CDDP in cervical cancer cells. We also present novel findings on the suppression of β-catenin and its downstream signaling components by PARP-1 inhibitor.
#: 5μM of CDDP was used both alone and in combination with PJ34; ##: A gradient of CDDP from 0-15μM was used to evaluate the combined effect of PJ34 and CDDP on IC50 value of CDDP. p: *<0.05, **<0.01. (H): HeLa; (S): SiHa.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
All India Institute of Medical Sciences.
Disclosure
All authors have declared no conflicts of interest.Table: 67P
Combined effect of PJ34 and CDDP on cisplatin sensitivity in cervical cancer cell lines
Cancer cell parameter | Only CDDP (10μM) | Only PJ34 (10μM) | CDDP(10μM) + PJ34(10μM) | p value/fold difference |
---|---|---|---|---|
Clonogenic formation fraction# | 0.23 ± 0.08 (H) 0.31± 0.06 (S) | 0.67 ± 0.09 (H) 0.65 ± 0.01 (S) | 0.13 ± 0.05 (H) 0.15 ± 0.07 (S) | * (H) * (S) |
Fold migration | 0.71 ± 0.06 (H) 0.75 ± 0.03 (S) | 0.89 ± 0.07 (H) 0.99 ± 0.08 (S) | 0.54 ± 0.05 (H) 0.34 ± 0.02 (S) | ** (H) * (S) |
Relative invasion | 43.4 ± 2.25 (H) 47.9 ± 7.07 (S) | 66.6 ± 5.94 (H) 70.5 ± 5.74 (S) | 15.8 ± 2.81 (H) 23.4± 4.13 (S) | ** (H) ** (S) |
IC50 value## | 8.25μM (H) 10.8μM (S) | 31.5μM (H) 33.0μM (S) | 3.6μM (H) 3.4μM (S) | 2.29 fold 3.18 fold |
Resources from the same session
5255 - [18F]-FDG PET/CT in predicting PD-L1 status in nasopharyngeal carcinoma
Presenter: Liang Zhao
Session: Poster Display session 1
Resources:
Abstract
4910 - Expression of PD-L1 in Chinese Patients with Common Cancers
Presenter: Min Zheng
Session: Poster Display session 1
Resources:
Abstract
4227 - The clearance of EGF by tumor-associated macrophages is suppressed by chemotherapeutic agent cisplatin
Presenter: Irina Larionova
Session: Poster Display session 1
Resources:
Abstract
5222 - VHIO-300 and a thousand one nights, a tale of Precision Medicine
Presenter: Ginevra Caratù
Session: Poster Display session 1
Resources:
Abstract
5668 - Matched Whole-Genome Sequencing and Whole-Exome Sequencing with Circulating Tumor DNA (ctDNA) Analysis are complementary modalities in clinical practice
Presenter: Robin Imperial
Session: Poster Display session 1
Resources:
Abstract
5772 - Exploring the role of genes associated with familial cancer syndromes on the development of multiple primary tumors
Presenter: Atanaska Mitkova
Session: Poster Display session 1
Resources:
Abstract
4784 - Doxorubicin resistance: early and advanced tumors can use two different strategies based on initial and profound abnormalities in microRNA expression signature
Presenter: Volodymyr Halytskiy
Session: Poster Display session 1
Resources:
Abstract
3456 - From tumor transcriptomes to underlying cell type proportions to better predict prognosis and response to treatments
Presenter: Yuna Blum
Session: Poster Display session 1
Resources:
Abstract
4976 - Optimization of automated germline DNA extraction from non-tumoral formalin-fixed paraffin embedded (FFPE) tissues
Presenter: Omar Youssef
Session: Poster Display session 1
Resources:
Abstract
4242 - HIV, HBV and HCV screening practices in oncology: a cross-sectional interregional survey
Presenter: Isabelle Poizot-Martin
Session: Poster Display session 1
Resources:
Abstract