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.

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.

• Authors: Sivalokanathan Sarveswaran, Ritisha Ghosh, Shravan Morisetty, Jagadananda Ghosh
• Journal: PloS one (PLoS One) Vol. 10 Issue 4 Pg. e0122805 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25875826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Indoles
• Leukotriene Antagonists
• Quinolines
• MK 0591
• Proto-Oncogene Proteins c-akt

Topics

• 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)