title: 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: Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States of America.
authors: Sivalokanathan
authors: S
authors: Sarveswaran
authors: Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States of America.
authors: Ritisha
authors: R
authors: Ghosh
authors: Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States of America.
authors: Shravan
authors: S
authors: Morisetty
authors: Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States of America; Josephine Ford Cancer Center, Henry Ford Health System, Detroit, MI 48202, United States of America.
authors: Jagadananda
authors: J
authors: Ghosh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D020024:Leukotriene Antagonists / Q000008:administration & dosage*; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011804:Quinolines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007211:Indoles; D020024:Leukotriene Antagonists; D011804:Quinolines; C078266:MK 0591; D051057:Proto-Oncogene Proteins c-akt