Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells

Detalhes bibliográficos
Autor(a) principal: Silva, João P. N.
Data de Publicação: 2023
Outros Autores: Monteiro, L., Silva, Patrícia M.A., Bousbaa, Hassan
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.48797/sl.2023.25
Resumo: Background: Head and neck cancer is the seventh most prevalent cancer worldwide and it includes oral cancer [1]. Approximately 90% of all oral cancers are oral squamous cell carcinomas [2,3]. Despite their promising preclinical results, the inhibitors of mitotic kinesins and kinases failed in clinical trials, probably because they are not too effective in inducing apoptosis when used in monotherapy [4,5]. Thus, apoptotic pathway in cell treated with mitotic kinesin and kinase inhibitors may be a strategy to improve the effectiveness of these antimitotic agents. Objective: kinesin spindle protein (KSP) is involved in chromosome segregation and its inhibition results in the formation of monopolar spindles, inducing a mitotic delay. Aurora B is involved in correcting errors in chromosome attachment to the mitotic spindle, and its inhibition leads to mitotic exit with chromosome missegregation. The objective of this study is to assess the antitumor potential of combining a KSP or an Aurora B inhibitor with a BCL-2 family inhibitor in oral cancer. Methods: To evaluate the cytotoxic activity of the inhibitors, the IC50 was determined by the MTT assay. Using the Combenefit software, the combinations corresponding to the lowest concentration of the drugs that resulted in the greatest cytotoxic effect were selected. Cell death was assessed by flow cytometry, using annexinV/PI staining. Cell fate after combination treatment was monitored and characterized by time-lapse microscopy. Results: Both anti-KSP/anti-BCL2 and anti-Aurora B/anti-BCL2 combinations showed synergistic effects with increased cytotoxic activity. The anti-KSP/anti-BCL2 combination showed an exacerbation of apoptosis during mitotic arrest, while the anti-Aurora B/anti-BCL2 combination led to increased postmitotic death. Conclusions: Our data demonstrate that the combination of a BCL2 family inhibitor with either a KSP or an Aurora B inhibitor may be potentially useful as treatment strategies against oral cancer.
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spelling Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cellsPosterBackground: Head and neck cancer is the seventh most prevalent cancer worldwide and it includes oral cancer [1]. Approximately 90% of all oral cancers are oral squamous cell carcinomas [2,3]. Despite their promising preclinical results, the inhibitors of mitotic kinesins and kinases failed in clinical trials, probably because they are not too effective in inducing apoptosis when used in monotherapy [4,5]. Thus, apoptotic pathway in cell treated with mitotic kinesin and kinase inhibitors may be a strategy to improve the effectiveness of these antimitotic agents. Objective: kinesin spindle protein (KSP) is involved in chromosome segregation and its inhibition results in the formation of monopolar spindles, inducing a mitotic delay. Aurora B is involved in correcting errors in chromosome attachment to the mitotic spindle, and its inhibition leads to mitotic exit with chromosome missegregation. The objective of this study is to assess the antitumor potential of combining a KSP or an Aurora B inhibitor with a BCL-2 family inhibitor in oral cancer. Methods: To evaluate the cytotoxic activity of the inhibitors, the IC50 was determined by the MTT assay. Using the Combenefit software, the combinations corresponding to the lowest concentration of the drugs that resulted in the greatest cytotoxic effect were selected. Cell death was assessed by flow cytometry, using annexinV/PI staining. Cell fate after combination treatment was monitored and characterized by time-lapse microscopy. Results: Both anti-KSP/anti-BCL2 and anti-Aurora B/anti-BCL2 combinations showed synergistic effects with increased cytotoxic activity. The anti-KSP/anti-BCL2 combination showed an exacerbation of apoptosis during mitotic arrest, while the anti-Aurora B/anti-BCL2 combination led to increased postmitotic death. Conclusions: Our data demonstrate that the combination of a BCL2 family inhibitor with either a KSP or an Aurora B inhibitor may be potentially useful as treatment strategies against oral cancer.IUCS-CESPU Publishing2023-04-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.48797/sl.2023.25https://doi.org/10.48797/sl.2023.25Scientific Letters; Vol. 1 No. Sup 1 (2023)2795-5117reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAPenghttps://publicacoes.cespu.pt/index.php/sl/article/view/25https://publicacoes.cespu.pt/index.php/sl/article/view/25/41Copyright (c) 2023 João P. N. Silva, L. Monteiro, Patrícia M.A. Silva, Hassan Bousbaainfo:eu-repo/semantics/openAccessSilva, João P. N.Monteiro, L.Silva, Patrícia M.A.Bousbaa, Hassan2023-04-29T08:45:54Zoai:publicacoes.cespu.pt:article/25Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T17:50:20.458797Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
title Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
spellingShingle Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
Silva, João P. N.
Poster
title_short Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
title_full Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
title_fullStr Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
title_full_unstemmed Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
title_sort Co-inhibition of mitotic kinesins and kinases with BCL-2 family inhibitors enhances cytotoxicity of oral cancer cells
author Silva, João P. N.
author_facet Silva, João P. N.
Monteiro, L.
Silva, Patrícia M.A.
Bousbaa, Hassan
author_role author
author2 Monteiro, L.
Silva, Patrícia M.A.
Bousbaa, Hassan
author2_role author
author
author
dc.contributor.author.fl_str_mv Silva, João P. N.
Monteiro, L.
Silva, Patrícia M.A.
Bousbaa, Hassan
dc.subject.por.fl_str_mv Poster
topic Poster
description Background: Head and neck cancer is the seventh most prevalent cancer worldwide and it includes oral cancer [1]. Approximately 90% of all oral cancers are oral squamous cell carcinomas [2,3]. Despite their promising preclinical results, the inhibitors of mitotic kinesins and kinases failed in clinical trials, probably because they are not too effective in inducing apoptosis when used in monotherapy [4,5]. Thus, apoptotic pathway in cell treated with mitotic kinesin and kinase inhibitors may be a strategy to improve the effectiveness of these antimitotic agents. Objective: kinesin spindle protein (KSP) is involved in chromosome segregation and its inhibition results in the formation of monopolar spindles, inducing a mitotic delay. Aurora B is involved in correcting errors in chromosome attachment to the mitotic spindle, and its inhibition leads to mitotic exit with chromosome missegregation. The objective of this study is to assess the antitumor potential of combining a KSP or an Aurora B inhibitor with a BCL-2 family inhibitor in oral cancer. Methods: To evaluate the cytotoxic activity of the inhibitors, the IC50 was determined by the MTT assay. Using the Combenefit software, the combinations corresponding to the lowest concentration of the drugs that resulted in the greatest cytotoxic effect were selected. Cell death was assessed by flow cytometry, using annexinV/PI staining. Cell fate after combination treatment was monitored and characterized by time-lapse microscopy. Results: Both anti-KSP/anti-BCL2 and anti-Aurora B/anti-BCL2 combinations showed synergistic effects with increased cytotoxic activity. The anti-KSP/anti-BCL2 combination showed an exacerbation of apoptosis during mitotic arrest, while the anti-Aurora B/anti-BCL2 combination led to increased postmitotic death. Conclusions: Our data demonstrate that the combination of a BCL2 family inhibitor with either a KSP or an Aurora B inhibitor may be potentially useful as treatment strategies against oral cancer.
publishDate 2023
dc.date.none.fl_str_mv 2023-04-21
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.uri.fl_str_mv https://doi.org/10.48797/sl.2023.25
https://doi.org/10.48797/sl.2023.25
url https://doi.org/10.48797/sl.2023.25
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv https://publicacoes.cespu.pt/index.php/sl/article/view/25
https://publicacoes.cespu.pt/index.php/sl/article/view/25/41
dc.rights.driver.fl_str_mv Copyright (c) 2023 João P. N. Silva, L. Monteiro, Patrícia M.A. Silva, Hassan Bousbaa
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Copyright (c) 2023 João P. N. Silva, L. Monteiro, Patrícia M.A. Silva, Hassan Bousbaa
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv IUCS-CESPU Publishing
publisher.none.fl_str_mv IUCS-CESPU Publishing
dc.source.none.fl_str_mv Scientific Letters; Vol. 1 No. Sup 1 (2023)
2795-5117
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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