Reversal of resistance to cytotoxic cancer therapies: DHMEQ as a chemo-sensitizing and immuno-sensitizing agent.

ABSTRACT

The development of tumor cell resistance to conventional therapeutics is a major clinical problem. There is an urgent need to develop novel therapeutics to overcome resistance and save patients from tumor recurrences. Novel therapeutics are currently being developed based on better understanding of the underlying molecular mechanisms that govern resistance and the identification of targets that control resistance. One of the major factors that controls resistance is the transcription factor nuclear factor kappaB (NF-kappaB) that has been shown to be constitutively activated in the majority of cancers and is responsible, in large part, for tumor cell survival, growth and direct activation of anti-apoptotic gene products. The development of non-toxic inhibitors of NF-kappaB activity may result in diminishing the anti-apoptotic threshold of resistant tumor cells and leading to inhibition of tumor cell growth and cell death or sensitization to the apoptotic effects of cytotoxic therapeutics. The novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), selectively prevents the translocation of NF-kappaB into the nucleus and, hence, prevents its various transcriptional functions. Thus, DHMEQ is unlike many other NF-kappaB inhibitors that target gene products of the NF-kappaB pathway and it is also unlike proteasome inhibitors that prevent the degradation of pIkappaB. DHMEQ is a small molecule shown to be non-toxic in mice and rodents and exerts direct anti-tumor effects in vitro and in vivo as well as significant chemo- and immuno-sensitizing activities in resistant tumor cells. The present review summarizes studies that have used DHMEQ as a novel anti-cancer agent.