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Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo.
Elango, Ramesh; Vishnubalaji, Radhakrishnan; Manikandan, Muthurangan; Binhamdan, Sarah Ibrahim; Siyal, Abdul-Aziz; Alshawakir, Yasser A; Alfayez, Musaad; Aldahmash, Abdullah; Alajez, Nehad M.
Afiliação
  • Elango R; Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
  • Vishnubalaji R; Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
  • Manikandan M; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Binhamdan SI; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Siyal AA; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Alshawakir YA; Experimental Surgery and Animal Lab, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Alfayez M; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Aldahmash A; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Alajez NM; Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia.
Sci Rep ; 9(1): 13696, 2019 09 23.
Article em En | MEDLINE | ID: mdl-31548560
Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRbSer795 protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Quinase 7 Ativada por Mitógeno / Inibidores de Proteínas Quinases / Proliferação de Células / Quinase 4 Dependente de Ciclina / Quinase 6 Dependente de Ciclina / Antineoplásicos Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Quinase 7 Ativada por Mitógeno / Inibidores de Proteínas Quinases / Proliferação de Células / Quinase 4 Dependente de Ciclina / Quinase 6 Dependente de Ciclina / Antineoplásicos Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2019 Tipo de documento: Article