Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer
Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 ( SOD1 ) in ovarian cancer is associated with a p...
Gespeichert in:
| Veröffentlicht in: | Cancer gene therapy 2023-11, Vol.30 (11), p.1554-1568 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1568 |
|---|---|
| container_issue | 11 |
| container_start_page | 1554 |
| container_title | Cancer gene therapy |
| container_volume | 30 |
| creator | Szénási, Attila Sivasudhan, Enakshi Du, Hong Zhang, Peizhuo Huang, Jie Zhang, Zhijun Rocha, Sonia Wang, Mu |
| description | Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (
SOD1
) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of
SOD1
via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of
SOD1
silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GO
PEI
-mPEG) nanoparticle was complexed with
SOD1
siRNA. GO
PEI
-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of
SOD1
mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPR
mt
) used as a reporter for their respective cytotoxicities.
SOD1
silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780
DDP
subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of
SOD1
as a chemosensitizer for platinum-resistant ovarian cancers. |
| doi_str_mv | 10.1038/s41417-023-00659-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2851869382</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2851869382</sourcerecordid><originalsourceid>FETCH-LOGICAL-c419t-2bfc5458ca792447d70075c13e7497f23e18bfc3820f12ae86b3c8a2a46b21253</originalsourceid><addsrcrecordid>eNp9kT1PHDEQhi2UCC4X_gAFspQmjYk_13aJCCFIKCAgteXzzd4Z7Xk39i4J_z6G40NKkWqKeeaZ0bwIHTB6xKgwX4pkkmlCuSCUNsoSvoNmTOqGKEXpOzSjllvCLBV76EMpd5TWpha7aE9oZbgVcobWtz6vYIxphW8uvzJ8Hz2-_nEc8e84rvHV6dlD50dY4lX2wxoS4P5PXAJOPvWDz2MMHRQcEx4qFtO0IRlKLKNPI-7vfY4-4eBTgPwRvW99V2D_uc7Rz2-ntyffycXl2fnJ8QUJktmR8EUblFQmeG25lHqpKdUqMAFaWt1yAcxURBhOW8Y9mGYhgvHcy2bBGVdijj5vvUPuf01QRreJJUDX-QT9VBw3ipnGVkFFP_2D3vVTTvW6ShmrrVH1SXPEt1TIfSkZWjfkuPH5wTHqHnNw2xxczcE95eAe1YfP6mmxgeXryMvjKyC2QKmttIL8tvs_2r-auZJL</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2889798529</pqid></control><display><type>article</type><title>Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Szénási, Attila ; Sivasudhan, Enakshi ; Du, Hong ; Zhang, Peizhuo ; Huang, Jie ; Zhang, Zhijun ; Rocha, Sonia ; Wang, Mu</creator><creatorcontrib>Szénási, Attila ; Sivasudhan, Enakshi ; Du, Hong ; Zhang, Peizhuo ; Huang, Jie ; Zhang, Zhijun ; Rocha, Sonia ; Wang, Mu</creatorcontrib><description>Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (
SOD1
) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of
SOD1
via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of
SOD1
silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GO
PEI
-mPEG) nanoparticle was complexed with
SOD1
siRNA. GO
PEI
-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of
SOD1
mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPR
mt
) used as a reporter for their respective cytotoxicities.
SOD1
silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780
DDP
subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of
SOD1
as a chemosensitizer for platinum-resistant ovarian cancers.</description><identifier>ISSN: 0929-1903</identifier><identifier>EISSN: 1476-5500</identifier><identifier>DOI: 10.1038/s41417-023-00659-2</identifier><identifier>PMID: 37582934</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13/106 ; 13/109 ; 13/31 ; 38/109 ; 42/41 ; 42/89 ; 631/154 ; 631/67/1059/2326 ; 64/60 ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biocompatibility ; Biomedical and Life Sciences ; Biomedicine ; Carcinoma, Ovarian Epithelial - genetics ; Cell Line, Tumor ; Cisplatin ; Cisplatin - pharmacology ; Cisplatin - therapeutic use ; Cytotoxicity ; Drug Resistance, Neoplasm - genetics ; Female ; Gene Expression ; Gene Therapy ; Graphene ; Graphite - metabolism ; Graphite - therapeutic use ; Humans ; Mice ; Nanoparticles ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Oxidative stress ; Patient care planning ; Phenotypes ; Platinum ; Platinum compounds ; Polyethylene Glycols ; Polyethyleneimine ; Protein folding ; Proteins ; RNA Interference ; RNA, Small Interfering - genetics ; RNA-mediated interference ; siRNA ; Superoxide dismutase ; Superoxide Dismutase-1 - genetics ; Superoxide Dismutase-1 - metabolism ; Superoxide Dismutase-1 - therapeutic use ; Therapeutic applications</subject><ispartof>Cancer gene therapy, 2023-11, Vol.30 (11), p.1554-1568</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-2bfc5458ca792447d70075c13e7497f23e18bfc3820f12ae86b3c8a2a46b21253</citedby><cites>FETCH-LOGICAL-c419t-2bfc5458ca792447d70075c13e7497f23e18bfc3820f12ae86b3c8a2a46b21253</cites><orcidid>0009-0007-6078-7190 ; 0009-0007-3584-6873 ; 0000-0002-4484-4032</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41417-023-00659-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41417-023-00659-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37582934$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szénási, Attila</creatorcontrib><creatorcontrib>Sivasudhan, Enakshi</creatorcontrib><creatorcontrib>Du, Hong</creatorcontrib><creatorcontrib>Zhang, Peizhuo</creatorcontrib><creatorcontrib>Huang, Jie</creatorcontrib><creatorcontrib>Zhang, Zhijun</creatorcontrib><creatorcontrib>Rocha, Sonia</creatorcontrib><creatorcontrib>Wang, Mu</creatorcontrib><title>Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer</title><title>Cancer gene therapy</title><addtitle>Cancer Gene Ther</addtitle><addtitle>Cancer Gene Ther</addtitle><description>Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (
SOD1
) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of
SOD1
via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of
SOD1
silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GO
PEI
-mPEG) nanoparticle was complexed with
SOD1
siRNA. GO
PEI
-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of
SOD1
mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPR
mt
) used as a reporter for their respective cytotoxicities.
SOD1
silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780
DDP
subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of
SOD1
as a chemosensitizer for platinum-resistant ovarian cancers.</description><subject>13/106</subject><subject>13/109</subject><subject>13/31</subject><subject>38/109</subject><subject>42/41</subject><subject>42/89</subject><subject>631/154</subject><subject>631/67/1059/2326</subject><subject>64/60</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biocompatibility</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carcinoma, Ovarian Epithelial - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>Cisplatin - therapeutic use</subject><subject>Cytotoxicity</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Graphene</subject><subject>Graphite - metabolism</subject><subject>Graphite - therapeutic use</subject><subject>Humans</subject><subject>Mice</subject><subject>Nanoparticles</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Oxidative stress</subject><subject>Patient care planning</subject><subject>Phenotypes</subject><subject>Platinum</subject><subject>Platinum compounds</subject><subject>Polyethylene Glycols</subject><subject>Polyethyleneimine</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA-mediated interference</subject><subject>siRNA</subject><subject>Superoxide dismutase</subject><subject>Superoxide Dismutase-1 - genetics</subject><subject>Superoxide Dismutase-1 - metabolism</subject><subject>Superoxide Dismutase-1 - therapeutic use</subject><subject>Therapeutic applications</subject><issn>0929-1903</issn><issn>1476-5500</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kT1PHDEQhi2UCC4X_gAFspQmjYk_13aJCCFIKCAgteXzzd4Z7Xk39i4J_z6G40NKkWqKeeaZ0bwIHTB6xKgwX4pkkmlCuSCUNsoSvoNmTOqGKEXpOzSjllvCLBV76EMpd5TWpha7aE9oZbgVcobWtz6vYIxphW8uvzJ8Hz2-_nEc8e84rvHV6dlD50dY4lX2wxoS4P5PXAJOPvWDz2MMHRQcEx4qFtO0IRlKLKNPI-7vfY4-4eBTgPwRvW99V2D_uc7Rz2-ntyffycXl2fnJ8QUJktmR8EUblFQmeG25lHqpKdUqMAFaWt1yAcxURBhOW8Y9mGYhgvHcy2bBGVdijj5vvUPuf01QRreJJUDX-QT9VBw3ipnGVkFFP_2D3vVTTvW6ShmrrVH1SXPEt1TIfSkZWjfkuPH5wTHqHnNw2xxczcE95eAe1YfP6mmxgeXryMvjKyC2QKmttIL8tvs_2r-auZJL</recordid><startdate>20231101</startdate><enddate>20231101</enddate><creator>Szénási, Attila</creator><creator>Sivasudhan, Enakshi</creator><creator>Du, Hong</creator><creator>Zhang, Peizhuo</creator><creator>Huang, Jie</creator><creator>Zhang, Zhijun</creator><creator>Rocha, Sonia</creator><creator>Wang, Mu</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0009-0007-6078-7190</orcidid><orcidid>https://orcid.org/0009-0007-3584-6873</orcidid><orcidid>https://orcid.org/0000-0002-4484-4032</orcidid></search><sort><creationdate>20231101</creationdate><title>Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer</title><author>Szénási, Attila ; Sivasudhan, Enakshi ; Du, Hong ; Zhang, Peizhuo ; Huang, Jie ; Zhang, Zhijun ; Rocha, Sonia ; Wang, Mu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-2bfc5458ca792447d70075c13e7497f23e18bfc3820f12ae86b3c8a2a46b21253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>13/106</topic><topic>13/109</topic><topic>13/31</topic><topic>38/109</topic><topic>42/41</topic><topic>42/89</topic><topic>631/154</topic><topic>631/67/1059/2326</topic><topic>64/60</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biocompatibility</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Carcinoma, Ovarian Epithelial - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cisplatin</topic><topic>Cisplatin - pharmacology</topic><topic>Cisplatin - therapeutic use</topic><topic>Cytotoxicity</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Graphene</topic><topic>Graphite - metabolism</topic><topic>Graphite - therapeutic use</topic><topic>Humans</topic><topic>Mice</topic><topic>Nanoparticles</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Oxidative stress</topic><topic>Patient care planning</topic><topic>Phenotypes</topic><topic>Platinum</topic><topic>Platinum compounds</topic><topic>Polyethylene Glycols</topic><topic>Polyethyleneimine</topic><topic>Protein folding</topic><topic>Proteins</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA-mediated interference</topic><topic>siRNA</topic><topic>Superoxide dismutase</topic><topic>Superoxide Dismutase-1 - genetics</topic><topic>Superoxide Dismutase-1 - metabolism</topic><topic>Superoxide Dismutase-1 - therapeutic use</topic><topic>Therapeutic applications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Szénási, Attila</creatorcontrib><creatorcontrib>Sivasudhan, Enakshi</creatorcontrib><creatorcontrib>Du, Hong</creatorcontrib><creatorcontrib>Zhang, Peizhuo</creatorcontrib><creatorcontrib>Huang, Jie</creatorcontrib><creatorcontrib>Zhang, Zhijun</creatorcontrib><creatorcontrib>Rocha, Sonia</creatorcontrib><creatorcontrib>Wang, Mu</creatorcontrib><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szénási, Attila</au><au>Sivasudhan, Enakshi</au><au>Du, Hong</au><au>Zhang, Peizhuo</au><au>Huang, Jie</au><au>Zhang, Zhijun</au><au>Rocha, Sonia</au><au>Wang, Mu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer</atitle><jtitle>Cancer gene therapy</jtitle><stitle>Cancer Gene Ther</stitle><addtitle>Cancer Gene Ther</addtitle><date>2023-11-01</date><risdate>2023</risdate><volume>30</volume><issue>11</issue><spage>1554</spage><epage>1568</epage><pages>1554-1568</pages><issn>0929-1903</issn><eissn>1476-5500</eissn><abstract>Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (
SOD1
) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of
SOD1
via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of
SOD1
silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GO
PEI
-mPEG) nanoparticle was complexed with
SOD1
siRNA. GO
PEI
-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of
SOD1
mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPR
mt
) used as a reporter for their respective cytotoxicities.
SOD1
silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780
DDP
subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of
SOD1
as a chemosensitizer for platinum-resistant ovarian cancers.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>37582934</pmid><doi>10.1038/s41417-023-00659-2</doi><tpages>15</tpages><orcidid>https://orcid.org/0009-0007-6078-7190</orcidid><orcidid>https://orcid.org/0009-0007-3584-6873</orcidid><orcidid>https://orcid.org/0000-0002-4484-4032</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0929-1903 |
| ispartof | Cancer gene therapy, 2023-11, Vol.30 (11), p.1554-1568 |
| issn | 0929-1903 1476-5500 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2851869382 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 13/106 13/109 13/31 38/109 42/41 42/89 631/154 631/67/1059/2326 64/60 Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biocompatibility Biomedical and Life Sciences Biomedicine Carcinoma, Ovarian Epithelial - genetics Cell Line, Tumor Cisplatin Cisplatin - pharmacology Cisplatin - therapeutic use Cytotoxicity Drug Resistance, Neoplasm - genetics Female Gene Expression Gene Therapy Graphene Graphite - metabolism Graphite - therapeutic use Humans Mice Nanoparticles Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Oxidative stress Patient care planning Phenotypes Platinum Platinum compounds Polyethylene Glycols Polyethyleneimine Protein folding Proteins RNA Interference RNA, Small Interfering - genetics RNA-mediated interference siRNA Superoxide dismutase Superoxide Dismutase-1 - genetics Superoxide Dismutase-1 - metabolism Superoxide Dismutase-1 - therapeutic use Therapeutic applications |
| title | Targeting SOD1 via RNAi with PEGylated graphene oxide nanoparticles in platinum-resistant ovarian cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T21%3A29%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20SOD1%20via%20RNAi%20with%20PEGylated%20graphene%20oxide%20nanoparticles%20in%20platinum-resistant%20ovarian%20cancer&rft.jtitle=Cancer%20gene%20therapy&rft.au=Sz%C3%A9n%C3%A1si,%20Attila&rft.date=2023-11-01&rft.volume=30&rft.issue=11&rft.spage=1554&rft.epage=1568&rft.pages=1554-1568&rft.issn=0929-1903&rft.eissn=1476-5500&rft_id=info:doi/10.1038/s41417-023-00659-2&rft_dat=%3Cproquest_cross%3E2851869382%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2889798529&rft_id=info:pmid/37582934&rfr_iscdi=true |