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: Yen-Ling Lin, Yasemin Yuksel Durmaz, Jacques E Nör, Mohamed E H ElSayed
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 10 Issue 7 Pg. 2730-8 (Jul 01 2013) ISSN: 1543-8392 [Electronic] United States
• PMID: 23734725 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Gossypol
• gossypol acetic acid

Topics

• Apoptosis (genetics, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Gossypol (analogs & derivatives, pharmacology)
• Head and Neck Neoplasms (genetics, metabolism, pathology)
• Humans
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA Interference (physiology)
• RNA, Small Interfering