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
3683 - Impact of Radiotherapy on efficacy of anti-programmed death 1 (PD-1) antibodies in metastatic NSCLC
Presenter: Evangeline Samuel
Session: Poster Display session 1
Resources:
Abstract
3924 - Pembrolizumab frontline monotherapy in patients with NSCLC and high PD-L1 expression: Real World Data from a European Cohort with focus on subgroups of interest
Presenter: Giannis Mountzios
Session: Poster Display session 1
Resources:
Abstract
3970 - Patients with metastatic non-small cell lung cancer and PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Martin Sebastian
Session: Poster Display session 1
Resources:
Abstract
5350 - The efficacy and safety of pembrolizumab as a first-line therapy in PD-L1 50% positive advanced NSCLC (HOPE-001)
Presenter: Motohiro Tamiya
Session: Poster Display session 1
Resources:
Abstract
3832 - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)
Presenter: Giulio Metro
Session: Poster Display session 1
Resources:
Abstract
4082 - Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first- or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)
Presenter: Riyaz Shah
Session: Poster Display session 1
Resources:
Abstract
2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations
Presenter: Kazuto Nishio
Session: Poster Display session 1
Resources:
Abstract
2911 - Apatinib combined with EGFR - TKI in treating advanced non-small cell lung cancer with EGFR - TKI resistance
Presenter: Ruifen Tian
Session: Poster Display session 1
Resources:
Abstract
2100 - Updated analysis of a phase I trial of afatinib (Afa) and bevacizumab (Bev) in chemo-naïve patients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-mutations: OLCSG1404
Presenter: Takashi Ninomiya
Session: Poster Display session 1
Resources:
Abstract
4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract