title: Synergistic combination of small molecule inhibitor and RNA interference against antiapoptotic Bcl-2 protein in head and neck cancer cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Yuksel Durmaz
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: ElSayed
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D006072:Gossypol; C028178:gossypol acetic acid