Augmentation of the Differentiation Response to Antitumor Antimalarials
Abstract
An impeding Challenge to breast cancer drug therapies is the availability of more effective and less toxic chemotherapeutic agents that do not relay harm to neighboring normal breast cells and tissues. We have shown that the quinoline antimalarials chloroquine (CO) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-10A cells. The purpose of this project is to derive more efficacious antitumor agents and enhance the differentiation response by using CQ and HCQ in combination with the demethylating agent, 5-Aza-2'-deoxycytidine (5-Aza-dC), or with the differentiating agent, all-trans-Retinoic acid (ATRA). Cell survival, cellular differentiation, and histone H4 acetylation status were measured. Future experiments will analyze histone deacetylase (HDAC) protein degradation and the acetylation levels at specific lysine sites in order to generate the overall histone acetylation profiles for the drug combinations. Results show that the combination of 5-Aza-dC or ATRA with the antimalarials sensitized both the MDA- MB-23l and MCF-7 breast cancer cell lines to growth inhibition, enhanced cellular differentiation, and elevated histone H4 acetylation. These results support the use of CQ or HCQ with other tumor differentiating agents in combination to provide a more effective and less toxic therapeutic regimen for breast cancer intervention.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA419295
Entities
People
- Jeannine S. Strobl
- Rayhana Rahim
Organizations
- West Virginia University