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
1267 - Genetic landscape of KEAP1 and NFE2L2 mutated cancers from the AACR GENIE database
Presenter: Mark Zaki
Session: Poster Display session 1
Resources:
Abstract
878 - β-arrestin1 is involved in the Ras-induced malignant transformation
Presenter: Takashi Shibano
Session: Poster Display session 1
Resources:
Abstract
4143 - Incidence of second cancer among PLWHIV: retrospective observational study of a series of 601 patients in the French CANCERVIH network
Presenter: Jean-Philippe Spano
Session: Poster Display session 1
Resources:
Abstract
5145 - A challenging task – Identifying carcinoma of unknown primary (CUP) patients according to ESMO guidelines: the CUPISCO trial experience
Presenter: Chantal Pauli
Session: Poster Display session 1
Resources:
Abstract
1737 - Incidence and Outcome of chronic lymphocytic leukemia with Deletion 17p: An Indian experience; challenges and opportunities
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
2596 - Driving solo? Investigation into collaborating mutations in SDH-deficient neoplasia
Presenter: Jonathan Killian
Session: Poster Display session 1
Resources:
Abstract
1499 - The potential of a novel antiangiogenic VEGFR1-D2 binding peptide in oncology therapeutics
Presenter: Afsaneh Sadre Momtaz
Session: Poster Display session 1
Resources:
Abstract
1775 - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors
Presenter: Mayu Yunokawa
Session: Poster Display session 1
Resources:
Abstract
4584 - First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumors: Dose-optimization cohorts
Presenter: Emiliano Calvo
Session: Poster Display session 1
Resources:
Abstract
3620 - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours
Presenter: Wolfgang Wick
Session: Poster Display session 1
Resources:
Abstract