Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor.

Author(s): Xu W, Ngo L, Perez G, Dokmanovic M, Marks PA

Affiliation(s): Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Publication date & source: 2006-10-17, Proc Natl Acad Sci U S A., 103(42):15540-5. Epub 2006 Oct 9.

Publication type: Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

There is a great need to develop better mechanism-based therapies for prostate cancer. In this investigation, we studied four human prostate cancer cell lines, LNCaP, DU145, LAPC4, and PC3, which differ in response to the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (vorinostat), a new anticancer drug. Examining the role of intrinsic mitochondrial caspase-dependent apoptosis and caspase-independent, reactive oxygen species (ROS) facilitated cell death, has provided an understanding of mechanisms that may determine the varied response to the histone deacetylase inhibitor. We found striking differences among these cancer cells in constitutive expression and response to suberoylanilide hydroxamic acid in levels of antiapoptotic and proapoptotic proteins, mitochondria membrane integrity, activation of caspases, ROS accumulation, and expression of thioredoxin, the major scavenger of ROS. Identifying these differences can have predictive value in assessing therapeutic response and identifying targets to enhance therapeutic efficacy.