Chemosensitization and Immunosensitization of Resistant Cancer Cells to Apoptosis and Inhibition of Metastasis by the Specific NF-κB Inhibitor DHMEQ

Alina      Katsman; Kazuo      Umezawa; Benjamin      Bonavida

Abstract

Tumors develop resistance to cytotoxic apoptotic stimuli induced by various chemotherapeutic drugs and immunotherapies. Therefore, there is a need to overcome chemo- and immuno-resistance of tumors through the development of small molecules, as sensitizing agents, aimed at targeting gene products that regulate the apoptotic pathways and allow therapeutics to be effective. The constitutively activated NF-κB (nuclear factor kappa B) signaling pathway is involved in cell survival, inflammation and metastasis and is invariably constitutively activated in most cancers. Consequently, NF-κB is intimately involved in the regulation of resistance to cytotoxic drugs. A novel NF-κB inhibitor, DHMEQ (dehydroxymethylepoxyquinomicin), inhibits the translocation of NF-κB into the nucleus as well as inhibits DNA binding of NF-κB components and was shown to be a potent chemo- and immuno-sensitizing agent and in combination with cytotoxic therapeutics resulted in significant reversal of resistance and tumor cell death. This review will present various lines of evidence supporting the therapeutic efficacy of DHMEQ when used in combination with conventional/new cytotoxic drugs in the treatment of resistant tumor cells as well as in the prevention of metastasis.

Keywords: Chemo-immuno sensitization, overcoming resistance, regulation of apoptotic pathways, metastasis, immunosurveillance cancer gene RKIP, Snail, NF-κB inhibition, DHMEQ