Recommended Citation
Sarveswaran S, Ghosh R, Morisetty S, and Ghosh J. MK591, a second generation leukotriene biosynthesis inhibitor, prevents invasion and induces apoptosis in the bone-invading C4-2B human prostate cancer cells: implications for the treatment of castration-resistant, bone-metastatic prostate cancer. PLoS One 2015; 10(4):e0122805.
Document Type
Article
Publication Date
1-1-2015
Publication Title
PLoS One
Abstract
Castration-resistant prostate cancer (CRPC) is a major clinical challenge for which no cure is currently available primarily because of the lack of proper understanding about appropriate molecular target(s). Previously we observed that inhibition of 5-lipoxygenase (5-Lox) activity induces apoptosis in some types of prostate cancer cells, suggesting an important role of 5-Lox in the viability of prostate cancer cells. However, nothing is known about the role of 5-Lox in the survival of castration-resistant, metastatic prostate cancer cells. Thus, we tested the effects of MK591, a second-generation, specific inhibitor of 5-Lox activity, on the viability and metastatic characteristics of CRPC cells. We observed that MK591 effectively kills the bone-invading C4-2B human prostate cancer cells (which bear characteristics of CRPC), but does not affect normal, non-cancer fibroblasts (which do not express 5-Lox) in the same experimental conditions. We also observed that MK591 dramatically inhibits the in vitro invasion and soft-agar colony formation of C4-2B cells. Interestingly, we found that treatment with MK591 dramatically down-regulates the expression of c-Myc and its targets at sub-lethal doses. In light of frequent over-activation of c-Myc in a spectrum of aggressive cancers (including CRPC), and the challenges associated with inhibition of c-Myc (because of its non-enzymatic nature), our novel findings of selective killing, and blockade of invasive and soft-agar colony-forming abilities of the castration-resistant, bone-metastatic C4-2B prostate cancer cells by MK591, open up a new avenue to attack CRPC cells for better management of advanced prostate cancer while sparing normal, non-cancer body cells.
Medical Subject Headings
Apoptosis/drug effects; Bone Neoplasms/drug therapy/pathology/secondary; Cell Line; Tumor; Humans; Indoles/administration & dosage; Leukotriene Antagonists/administration & dosage; Male; Neoplasm Invasiveness/pathology; Neoplasm Metastasis; Prostate/drug effects/pathology; Prostatic Neoplasms; Castration-Resistant/drug therapy/pathology; Proto-Oncogene Proteins c-akt/biosynthesis; Quinolines/administration & dosage; Signal Transduction/drug effects
PubMed ID
25875826
Volume
10
Issue
4
First Page
e0122805
