Chemosensitization and immunosensitization of resistant cancer cells to apoptosis and inhibition of metastasis by the specific NF-kappaB inhibitor DHMEQ.
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-kappaB (nuclear factor kappa B) signaling pathway is involved in cell survival, inflammation and metastasis and is invariably constitutively activated in most cancers. Consequently, NF-kappaB is intimately involved in the regulation of resistance to cytotoxic drugs. A novel NF-kappaB inhibitor, DHMEQ (dehydroxymethylepoxyquinomicin), inhibits the translocation of NF-kappaB into the nucleus as well as inhibits DNA binding of NF-kappaB 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.
Katsman
Alina
A
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles CA 90095, USA. BBonavida@mednet.ucla.edu.
Umezawa
Kazuo
K
Bonavida
Benjamin
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin