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Conference Paper: Olaparib mediated DNA damage response and its resistant mechanism in cervical cancer cells

TitleOlaparib mediated DNA damage response and its resistant mechanism in cervical cancer cells
Authors
Issue Date2020
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
American Association for Cancer Research (AACR) Virtual Meeting II, 22-24 June 2020. Proceedings in Cancer Research, 2020, v. 80 n. 16, Suppl., abstract no. 2961 How to Cite?
AbstractCervical cancer is still the most common gynecologic cancer in developing countries. Olaparib is a poly-(ADR-ribose)-polymerase 1 (PARP1) inhibitor targeting at DNA strand break repair. However its efficacy in cervical cancer is unclear. This study aimed to evaluate the therapeutic potential of olaparib in cervical cancer. Olaparib remarkably reduced the PARylation activity and arrested cervical cancer cells at G2/M phase, and was associated with reduced level of a mitosis marker, phosphor-histone H3 as indicated by propidium iodide DNA staining and immunofluorescence. Cytotoxicity of olaparib against cervical cancer cells was determined by XTT assay with IC50 ranged from 35.49µM in C4I to 87.17µM in SiHa. The difference in olaparib sensitivity between C4I and SiHa was consistently demonstrated in annexin V based apoptotic assay, where a higher level of apoptotic response was found in C4I (21.12%) compared to SiHa (6.37%). Immunofluorescent staining and western blot for gH2AX clearly showed DNA double-strand break accumulation in both cell lines upon PARP1 blockade. Lower expression level of RAD51, a homologous recombination (HR) repair factor, was also observed in C4I, when compared to SiHa. Besides, gH2AX/RAD51 foci co-immunofluorescent line scan image analysis showed that there was reduced level of DNA damage recognition by RAD51 (26.80%), compared to SiHa (65.31%). These findings suggested that there was a reduced HR activity in C4I and might explain the higher sensitivity to olaparib compared to SiHa. We also demonstrated the therapeutic potential of olaparib in cervical cancer, and the rationale of using RAD51 as a predictive biomarker for olaparib sensitivity.
DescriptionVirtual Meeting II: E-Posters - Session PO.ET02.03 - Mechanisms of Drug Action 3 - Abstract no. 2961 / 8
Persistent Identifierhttp://hdl.handle.net/10722/284999
ISSN
2019 Impact Factor: 9.727
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorTse, KY-
dc.contributor.authorLiu, S-
dc.contributor.authorChan, KT-
dc.contributor.authorLee, HHY-
dc.contributor.authorIp, PPC-
dc.contributor.authorNgan, HYS-
dc.date.accessioned2020-08-07T09:05:25Z-
dc.date.available2020-08-07T09:05:25Z-
dc.date.issued2020-
dc.identifier.citationAmerican Association for Cancer Research (AACR) Virtual Meeting II, 22-24 June 2020. Proceedings in Cancer Research, 2020, v. 80 n. 16, Suppl., abstract no. 2961-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/284999-
dc.descriptionVirtual Meeting II: E-Posters - Session PO.ET02.03 - Mechanisms of Drug Action 3 - Abstract no. 2961 / 8-
dc.description.abstractCervical cancer is still the most common gynecologic cancer in developing countries. Olaparib is a poly-(ADR-ribose)-polymerase 1 (PARP1) inhibitor targeting at DNA strand break repair. However its efficacy in cervical cancer is unclear. This study aimed to evaluate the therapeutic potential of olaparib in cervical cancer. Olaparib remarkably reduced the PARylation activity and arrested cervical cancer cells at G2/M phase, and was associated with reduced level of a mitosis marker, phosphor-histone H3 as indicated by propidium iodide DNA staining and immunofluorescence. Cytotoxicity of olaparib against cervical cancer cells was determined by XTT assay with IC50 ranged from 35.49µM in C4I to 87.17µM in SiHa. The difference in olaparib sensitivity between C4I and SiHa was consistently demonstrated in annexin V based apoptotic assay, where a higher level of apoptotic response was found in C4I (21.12%) compared to SiHa (6.37%). Immunofluorescent staining and western blot for gH2AX clearly showed DNA double-strand break accumulation in both cell lines upon PARP1 blockade. Lower expression level of RAD51, a homologous recombination (HR) repair factor, was also observed in C4I, when compared to SiHa. Besides, gH2AX/RAD51 foci co-immunofluorescent line scan image analysis showed that there was reduced level of DNA damage recognition by RAD51 (26.80%), compared to SiHa (65.31%). These findings suggested that there was a reduced HR activity in C4I and might explain the higher sensitivity to olaparib compared to SiHa. We also demonstrated the therapeutic potential of olaparib in cervical cancer, and the rationale of using RAD51 as a predictive biomarker for olaparib sensitivity.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.relation.ispartofAmerican Association for Cancer Research (AACR) Virtual Meeting II-
dc.titleOlaparib mediated DNA damage response and its resistant mechanism in cervical cancer cells-
dc.typeConference_Paper-
dc.identifier.emailTse, KY: tseky@hku.hk-
dc.identifier.emailLiu, S: stephasl@hku.hk-
dc.identifier.emailChan, KT: ktchan66@hku.hk-
dc.identifier.emailLee, HHY: horlee@hkucc.hku.hk-
dc.identifier.emailIp, PPC: philipip@hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.authorityTse, KY=rp02391-
dc.identifier.authorityLiu, S=rp00372-
dc.identifier.authorityIp, PPC=rp01890-
dc.identifier.authorityNgan, HYS=rp00346-
dc.identifier.doi10.1158/1538-7445.AM2020-2961-
dc.identifier.hkuros312286-
dc.identifier.volume80-
dc.identifier.issue16, Suppl.-
dc.identifier.spageabstract no. 2961-
dc.identifier.epageabstract no. 2961-
dc.publisher.placeUnited States-

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