Cancer initiating cells have been described to be the only cell population with tumorigenic capacity in glioblastoma multiforme one of the most aggressive and untreatable cancers. intervention. and either alone or in combination with temozolomide [46]. This proteasome inhibitor is already approved for the treatment of patients with relapsed multiple myeloma or mantle cell lymphoma and a number of clinical trials are underway to determine the value of PS-341 as an effective therapy for malignant melanoma. Table 1 IKKβ small molecule inhibitors Figure 1 Response of solid tumor-derived cell lines to the IKKβ inhibitor EC-70124 Increasing evidence indicates the need of preclinical studies and clinical trials using Vicriviroc Malate potent and selective inhibitors of the kinase activity of IKKs to assure the specificity against a key pathway for a number of cancer cell types including glioblastoma. To this end there are undergoing clinical trials with novel IKK inhibitors such as SAR113945 a small molecule inhibitor from Sanofi-Aventis that is being evaluated in patients with knee osteoarthritis. This and other compounds that may pass the security stage could be adecuate candidates to be analyzed in cancer patients. UNANSWERED QUESTIONS AND FUTURE DIRECTIONS Increasing evidence support the key role of the NFκB signaling pathway in the pathogenesis and/or progression of GBM. There are numerous signaling routes that converge in the activation of NFκB but their relevance in GBM is usually poorly understood. Among these pathways DNA damage signaling appears to be constitutively activated in gliomas as documented by a number of markers mostly activation of ataxia telangiectasia mutated (ATM) kinase. Upon DNA damage this protein triggers multiple events to promote cell survival and facilitate repair. ATM Vicriviroc Malate augments cell survival by activating nuclear factor NFκB. Therefore further investigation around the association between ATM and NFκB in GBM might expand the targeted therapeutic options to avoid NFκB-dependent tumor cell survival and thus resistance to chemotherapeutic drugs. Aditionally a detailed study of the vast array of upstream regulators of NFκB in GBM cells is still to come. NFκB is emerging as a potential target for therapeutic intervention in GBM. Although a number of small molecule inhibitors of the NFκB pathway mainly inhibitors of IKK proteins are already available more specific inhibitors of IKKβ and other upstream kinases need to reach clinical studies to show their efficacy in GBM patients. Acknowledgments This work was supported by Instituto de Salud Carlos III (Spanish Ministry of Science and Development) grants RD06/0020/0074 (Red Temática de Investigación Cooperativa en Vicriviroc Malate Cáncer) PI07/0196 and PI10/02002 and grant API08/01 from Fundacion Marques de Valdecilla. Recommendations 1 Kumar A Takada Y Boriek AM Aggarwal BB. Nuclear factor-kappaB: its role in health and disease. J Mol Med. 2004;82:434-448. [PubMed] 2 Baldwin AS. Jr. Series introduction: the transcription aspect NF-kappaB and individual disease. J Clin Invest. 2001;107:3-6. [PMC free of charge content] [PubMed] 3 Lernbecher T Muller U Wirth T. Distinct NF-kappa B/Rel transcription factors are in charge of inducible and tissue-specific gene activation. Character. 1993;365:767-770. [PubMed] 4 Pasparakis M Luedde T Schmidt-Supprian M. Dissection from the NF-kappaB signalling cascade in transgenic and knockout mice. Cell Loss of life Differ. 2006;13:861-872. [PubMed] 5 Senftleben U Cao Y Xiao G Greten FR Krahn G Bonizzi G Chen Y Hu Y Fong A Sunlight SC Karin M. Activation by IKKalpha of another evolutionary Rabbit Polyclonal to iNOS (phospho-Tyr151). conserved NF-kappa B signaling pathway. Research. 2001;293:1495-1499. [PubMed] 6 Naugler WE Karin M. NF-kappaB and cancer-identifying systems and goals. Curr Opin Genet Dev. 2008;18:19-26. [PMC free of charge content] [PubMed] 7 Torres J Watt FM. Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3. Nat Cell Biol. 2008;10:194-201. [PubMed] 8 Wehling N Palmer GD Pilapil C Liu F Wells JW Muller PE Evans CH Porter RM. Tumor and interleukin-1beta necrosis aspect alpha inhibit chondrogenesis by individual mesenchymal stem cells through NF-kappaB-dependent pathways. Joint disease Rheum. 2009;60:801-812. [PMC free of charge content] [PubMed] 9 Youthful Kilometres Bartlett PF Vicriviroc Malate Coulson EJ. Neural progenitor Vicriviroc Malate number is normally controlled by nuclear factor-kappaB p50 and p65 subunit-dependent.