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
2066 - Second-line (2L) real-world treatment (tx) patterns and outcomes in patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC) treated with first line (1L) immuno-oncology (IO) monotherapy (mono tx)
Presenter: Denis Talbot
Session: Poster Display session 1
Resources:
Abstract
5919 - Real-world effectiveness of nivolumab monotherapy after prior systemic therapy in advanced non-small cell lung cancer (NSCLC) in the United States
Presenter: David Stenehjem
Session: Poster Display session 1
Resources:
Abstract
3368 - Pembrolizumab as first-line treatment in NSCLC with PD-L1 ≥50%: Real life results from an all-comer population
Presenter: Nikolaj Frost
Session: Poster Display session 1
Resources:
Abstract
3775 - Patients with metastatic non-small cell lung cancer without molecular alterations or PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Frank Griesinger
Session: Poster Display session 1
Resources:
Abstract
3926 - Impact of second-line (2L) immune checkpoint inhibitors (ICIs) on the treatment (Tx) of advanced non-small cell lung cancer (NSCLC) in a UK centre: a REAL-Oncology analysis from the I-O Optimise initiative
Presenter: Michael Snee
Session: Poster Display session 1
Resources:
Abstract
5068 - First line pembrolizumab for NSCLC with PD-L1 TPS > 50% in a first French real life cohort
Presenter: Karim Amrane
Session: Poster Display session 1
Resources:
Abstract
1182 - Interstitial lung disease induced by immune-checkpoint inhibitors correlates with prognosis of advanced non-small-cell lung cancer patients
Presenter: Teppei Sugano
Session: Poster Display session 1
Resources:
Abstract
2297 - Phase II study to evaluate the peripheral blood mononuclear cell biomarker for nivolumab efficacy on previously treated non-small cell lung cancer subjects (NEJ029B: IMMUNITY-ONE)
Presenter: Yosuke Kawashima
Session: Poster Display session 1
Resources:
Abstract
2739 - Efficacy and safety of nintedanib + docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Updated results of the ongoing non-interventional study (NIS) VARGADO (NCT02392455)
Presenter: Christian Grohe
Session: Poster Display session 1
Resources:
Abstract
1357 - Upfront atezolizumab chemoimmunotherapy-associated Immune-related adverse events in patients with advanced non-small cell lung cancer
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract