1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line
The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs)...
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| Veröffentlicht in: | International journal of molecular sciences 2022-07, Vol.23 (15), p.8105 |
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| creator | de Sousa Portilho, Adrhyann Jullyanne da Silva, Emerson Lucena Bezerra, Emanuel Cintra Austregésilo Moraes Rego Gomes, Carinne Borges de Souza Ferreira, Vitor de Moraes, Maria Elisabete Amaral da Rocha, David Rodrigues Burbano, Rommel Mário Rodriguez Moreira-Nunes, Caroline Aquino Montenegro, Raquel Carvalho |
| description | The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML. |
| doi_str_mv | 10.3390/ijms23158105 |
| format | Article |
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In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms23158105</identifier><identifier>PMID: 35897681</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Annexin V ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Blast crisis ; Cell cycle ; Cell Line, Tumor ; Cell membranes ; Chronic myeloid leukemia ; Comet assay ; Cytotoxicity ; Deoxyribonucleic acid ; Depolarization ; DNA ; DNA Damage ; DNA fragmentation ; Drug resistance ; Drug Resistance, Neoplasm - genetics ; Evaluation ; Flow cytometry ; Gene expression ; Genotoxicity ; Humans ; Imatinib ; Kinases ; Leukemia ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism ; Leukemia, Myeloid - drug therapy ; Leukocytes (mononuclear) ; Leukocytes, Mononuclear - metabolism ; Membrane potential ; Mitochondria ; Multidrug resistance ; Multidrug resistant organisms ; Myeloid leukemia ; Naphthoquinones - pharmacology ; Peripheral blood mononuclear cells ; Phenotypes ; Propidium iodide ; Tumor cell lines ; Tyrosine ; Up-Regulation</subject><ispartof>International journal of molecular sciences, 2022-07, Vol.23 (15), p.8105</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-a42bf1df6802e8b7926c3312bb0ca7f7db41dd98582a55454ae88404108ac6223</citedby><cites>FETCH-LOGICAL-c412t-a42bf1df6802e8b7926c3312bb0ca7f7db41dd98582a55454ae88404108ac6223</cites><orcidid>0000-0002-7928-8646 ; 0000-0001-5845-3481 ; 0000-0002-2166-766X ; 0000-0002-4872-234X ; 0000-0002-5761-8413</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330061/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330061/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35897681$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Sousa Portilho, Adrhyann Jullyanne</creatorcontrib><creatorcontrib>da Silva, Emerson Lucena</creatorcontrib><creatorcontrib>Bezerra, Emanuel Cintra Austregésilo</creatorcontrib><creatorcontrib>Moraes Rego Gomes, Carinne Borges de Souza</creatorcontrib><creatorcontrib>Ferreira, Vitor</creatorcontrib><creatorcontrib>de Moraes, Maria Elisabete Amaral</creatorcontrib><creatorcontrib>da Rocha, David Rodrigues</creatorcontrib><creatorcontrib>Burbano, Rommel Mário Rodriguez</creatorcontrib><creatorcontrib>Moreira-Nunes, Caroline Aquino</creatorcontrib><creatorcontrib>Montenegro, Raquel Carvalho</creatorcontrib><title>1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Sousa Portilho, Adrhyann Jullyanne</au><au>da Silva, Emerson Lucena</au><au>Bezerra, Emanuel Cintra Austregésilo</au><au>Moraes Rego Gomes, Carinne Borges de Souza</au><au>Ferreira, Vitor</au><au>de Moraes, Maria Elisabete Amaral</au><au>da Rocha, David Rodrigues</au><au>Burbano, Rommel Mário Rodriguez</au><au>Moreira-Nunes, Caroline Aquino</au><au>Montenegro, Raquel Carvalho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2022-07-23</date><risdate>2022</risdate><volume>23</volume><issue>15</issue><spage>8105</spage><pages>8105-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35897681</pmid><doi>10.3390/ijms23158105</doi><orcidid>https://orcid.org/0000-0002-7928-8646</orcidid><orcidid>https://orcid.org/0000-0001-5845-3481</orcidid><orcidid>https://orcid.org/0000-0002-2166-766X</orcidid><orcidid>https://orcid.org/0000-0002-4872-234X</orcidid><orcidid>https://orcid.org/0000-0002-5761-8413</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2022-07, Vol.23 (15), p.8105 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9330061 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Annexin V Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Blast crisis Cell cycle Cell Line, Tumor Cell membranes Chronic myeloid leukemia Comet assay Cytotoxicity Deoxyribonucleic acid Depolarization DNA DNA Damage DNA fragmentation Drug resistance Drug Resistance, Neoplasm - genetics Evaluation Flow cytometry Gene expression Genotoxicity Humans Imatinib Kinases Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism Leukemia, Myeloid - drug therapy Leukocytes (mononuclear) Leukocytes, Mononuclear - metabolism Membrane potential Mitochondria Multidrug resistance Multidrug resistant organisms Myeloid leukemia Naphthoquinones - pharmacology Peripheral blood mononuclear cells Phenotypes Propidium iodide Tumor cell lines Tyrosine Up-Regulation |
| title | 1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T03%3A29%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=1,4-Naphthoquinone%20(CNN1)%20Induces%20Apoptosis%20through%20DNA%20Damage%20and%20Promotes%20Upregulation%20of%20H2AFX%20in%20Leukemia%20Multidrug%20Resistant%20Cell%20Line&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=de%20Sousa%20Portilho,%20Adrhyann%20Jullyanne&rft.date=2022-07-23&rft.volume=23&rft.issue=15&rft.spage=8105&rft.pages=8105-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms23158105&rft_dat=%3Cproquest_pubme%3E2696010299%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2700722472&rft_id=info:pmid/35897681&rfr_iscdi=true |