MEK inhibition enhances bleomycin A5‐induced apoptosis in an oral cancer cell line: signaling mechanisms and therapeutic opportunities

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Abstract
Background:  Bleomycin A5 is an anti‐neoplastic glycoprotein antibiotic used for the treatment of various cancers. Previous work has shown that bleomycin A5 exerts its apoptotic effects on tumor cells. This was to study the signal transduction pathways that might exert the apoptotic effects of bleomycin A5 on tumor cells, as well as to examine the possibility of lower dosing of such drug in combinative treatment with other compounds in vitro.Methods:  Bleomycin A5 was applied on a human oral epidermoid carcinoma cell line, human oral epidermoid carcinoma (KB), and the apoptotic activity was determined by the presence of DNA fragmentation and 4,6‐diamidino‐2‐phenylindole (DAPI) nuclear staining. The signal transduction pathway was measured through Western blotting and in vitro kinase assay.Results:  The apoptotic effect was associated with the sustained activation of c‐Jun N‐terminal kinases (JNK) and the inhibition of extracellular signal‐regulated kinases1 (ERK1) and ‐2 activities, suggesting that JNK plays a positive role in the death process. ERK1 and ‐2 might exert a protection pathway from cell death. Here, it was determined that a combination treatment of bleomycin A5 and the MAP kinase‐ERK kinase (MEK) inhibitor, PD98059, could lead to enhanced apoptosis. The activities of ERK1 and ‐2 are required for cell survival signaling using stable cell clones expressing MEK1. Upon bleomycin A5 treatment, cells expressing MEK1 exhibited significant delays in the onset of apoptosis, where the presence of MEK1 inhibitor enhanced cell death. Moreover, the increased activity of ERK1 and ‐2 coincided with cell survival. The survival signals exerted by MEK1 most likely result from the activation of ERK1 and ‐2.Conclusions:  The apoptosis enhancement through such combinative treatment in vitro has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anti‐cancer treatments.