2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective
cyclooxygenase-2 (COX-2) inhibitor
celecoxib that lacks COX-2 inhibitory function. We and others have demonstrated that DMC, despite its inability to block COX-2, is able to potently mimic the antitumor effects of
celecoxib in vitro and in vivo. In this current study, we investigated whether DMC would also be able to inhibit the growth of highly
drug-resistant
tumor cell variants. We focused on human
multiple myeloma (MM) cells, as patients with MM frequently develop
drug-resistant disease and ultimately succumb to death. Here we show that DMC (and
celecoxib) inhibits the proliferation of various
multiple myeloma cell lines, including several (multi)
drug-resistant variants. Growth inhibition in
drug-sensitive and
drug-resistant cells is mediated via multiple effects, which include diminished
signal transducer and activator of transcription 3 (STAT-3) and
mitogen-activated
protein (
MAP) kinase kinase (
MEK) activity, reduced expression of
survivin and various
cyclins, and is followed by apoptotic cell death. Thus, our study demonstrates that inhibition of proliferation and induction of apoptosis by DMC (and
celecoxib) can be accomplished even in highly
drug-resistant
multiple myeloma cells, and that this effect is achieved via the blockage of multiple targets that are critical for
multiple myeloma cell growth and survival.