MK591, a leukotriene biosynthesis inhibitor, induces apoptosis in prostate cancer cells: synergistic action with LY294002, an inhibitor of phosphatidylinositol 3'-kinase.
MK591 is a synthetic compound which specifically inhibits the activity of 5-Lox and is currently under development for the treatment of asthma. We observed that human prostate cancer cells treated with MK591 undergo apoptosis within hours of treatment. Apoptosis involves severe morphological alteration, externalization of phosphatidyl-serine, cleavage of PARP, and degradation of chromatin-DNA. MK591 also induced rapid activation of the stress kinase, c-Jun N-terminal kinase (JNK), which plays an important role in the apoptosis process. The phosphatidylinositol 3'-kinase-Akt/protein kinase B (PI3K/Akt) axis is a well-known pro-survival pathway which prevents apoptosis through defined anti-apoptotic mechanisms in a variety of cancer cells. Interestingly, we observed that MK591 triggers apoptosis in prostate cancer cells without inhibition of PI3K-Akt, or ERK. Moreover, it was observed that MK591 and LY294002 (an inhibitor of PI3K) exert synergistic effect in inducing apoptosis in prostate cancer cells. Altogether, these findings indicate that 5-Lox inhibition-induced apoptosis in prostate cancer cells occurs without inhibition of PI3K-Akt, or ERK, and suggest for the existence of an Akt- and ERK-independent survival mechanism(s) in these cancer cells maintained via signals generated by metabolites of 5-Lox.
Sarveswaran
Sivalokanathan
S
Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI 48202, United States.
Myers
Charles E
CE
Ghosh
Jagadananda
J
D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology*
D002867:Chromones; D004791:Enzyme Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C078266:MK 0591; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one