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Synergistic combination of small molecule inhibitor and RNA interference against antiapoptotic Bcl-2 protein in head and neck cancer cells.
Lin, Yen-Ling; Yuksel Durmaz, Yasemin; Nör, Jacques E; ElSayed, Mohamed E H.
Afiliação
  • Lin YL; Department of Biomedical Engineering, Cellular Engineering & Nano-Therapeutics Laboratory, College of Engineering, ‡Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, and §Macromolecular Science and Engineering Program, University of Michigan , Ann Arbor, Michigan 48109, United States.
Mol Pharm ; 10(7): 2730-8, 2013 Jul 01.
Article em En | MEDLINE | ID: mdl-23734725
B-cell lymphoma 2 (Bcl-2) is an antiapoptotic protein that is overexpressed in head and neck squamous cell carcinomas, which has been implicated in development of radio- and chemoresistance. Small molecule inhibitors such as AT-101 (a BH3-mimetic drug) have been developed to inhibit the antiapoptotic activity of Bcl-2 proteins, which proved effective in restoring radio- and chemo-sensitivity in head and neck cancer cells. However, high doses of AT-101 are associated with gastrointestinal, hepatic, and fertility side effects, which prompted the search for other Bcl-2 inhibitors. Short interfering RNA (siRNA) proved to inhibit antiapoptotic Bcl-2 protein expression and trigger cancer cell death. However, transforming siRNA molecules into a viable therapy remains a challenge due to the lack of efficient and biocompatible carriers. We report the development of degradable star-shaped polymers that proved to condense anti-Bcl-2 siRNA into "smart" pH-sensitive and membrane-destabilizing particles that shuttle their cargo past the endosomal membrane and into the cytoplasm of head and neck cancer cells. Results show that "smart" anti-Bcl-2 particles reduced the mRNA and protein levels of antiapoptotic Bcl-2 protein in UM-SCC-17B cancer cells by 50-60% and 65-75%, respectively. Results also show that combining "smart" anti-Bcl-2 particles with the IC25 of AT-101 (inhibitory concentration responsible for killing 25% of the cells) synergistically inhibits cancer cell proliferation and increases cell apoptosis, which reduce the survival of UM-SCC-17B cancer cells compared to treatment with AT-101 alone. Results indicate the therapeutic benefit of combining siRNA-mediated knockdown of antiapoptotic Bcl-2 protein expression with low doses of AT-101 for inhibiting the growth of head and neck cancer cells.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Gossipol / Proteínas Proto-Oncogênicas c-bcl-2 / Neoplasias de Cabeça e Pescoço Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Gossipol / Proteínas Proto-Oncogênicas c-bcl-2 / Neoplasias de Cabeça e Pescoço Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article