Augmentation of the Differentiation Response to Antitumor Antimalarials
Abstract
We have shown that the quinoline antimalarials chioroquine (CQ) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-lOA cells. The purpose of this project is to derive more efficacious antitumor agents that enhance the differentiation response by using CQ and HCQ in combination with the demethylating agent, 5-Aza-2'-deoxycytidine (5-Aza-dC; Aza), or with the differentiating agent, all-trans-Retinoic acid (ATRA). Cell survival, cellular differentiation, histone H3 and/or histone H4 acetylation status, and HDAC protein and activity were measured to show that combination of Aza or ATRA with the quinolines augmented the antiproliferative effect, differentiation response, and acetylation status of either CQ or HCQ alone. A new and highly sensitive assay for histone acetylation by mass spectrometry was developed to illustrate the specific lysine sites that get modified (acetylated/deacetylated) by the most promising combination of chemotherapeutic agents. This approach will be pivotal in further developing more effective and less toxic therapeutic agents for breast cancer intervention.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2005
- Accession Number
- ADA441805
Entities
People
- Jeannine S. Strobl
- Rayhana Rahim
Organizations
- West Virginia University