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NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show that targeting Hsp90 does not interfere with SMC3-induced c-IAP1 degradation and TNF-α autocrine, the key processes for SMC3-induced cancer cell apoptosis. However, Hsp90 inhibitors effectively blocked SMC3-induced NF-κB activation through degradation of RIP1 and IKKβ, two key components of the NF-κB activation pathway, and reduced both the constitutive and SMC3-induced Akt activity through degradation of the Akt protein. Consistently, with the co-treatment of SMC3 and Hsp90 inhibitors, apoptosis was markedly sensitized and a synergistic cytotoxicity was observed. The results suggest that concurrent targeting c-IAP1 and Hsp90 by combination of SMC3 and Hsp90 inhibitors is an effective approach for improving the anticancer value of SMC3.

Importance of the Field: Nuclear factor kappa B (NF-kappaB) is activated by a variety of cancer-promoting agents. The reciprocal activation between NF-kappaB and inflammatory cytokines makes NF-kappaB important for inflammation-associated cancer development. Both the constitutive and anticancer therapeutic-induced NF-kappaB activation blunts the anticancer activities of the therapy. Elucidating the roles of NF-kappaB in cancer facilitates developing approaches for cancer prevention and therapy., Areas Covered in This Review: By searching PubMed, we summarize the progress of studies on NF-kappaB in carcinogenesis and cancer cells' drug resistance in recent 10 years., What the Reader Will Gain: The mechanisms by which NF-kappaB activation pathways are activated; the roles and mechanisms of NF-kappaB in cell survival and proliferation, and in carcinogenesis and cancer cells' response to therapy; recent development of NF-kappaB-modulating means and their application in cancer prevention and therapy., Take Home Message: NF-kappaB is involved in cancer development, modulating NF-kappaB activation pathways has important implications in cancer prevention and therapy. Due to the complexity of NF-kappaB roles in different cancers, careful evaluation of NF-kappaB's in each cancer type is crucial in this regard. More cancer cell-specific NF-kappaB inhibiting means are desired for improving anticancer efficacy and reducing systemic toxicity.

Smac mimetics are potential anticancer therapeutics selectively killing cancer cells through autocrine tumor necrosis factor (TNF)-mediated apoptosis pathway. Our recent study reveal that the Smac mimetic compound 3 (SMC3)-activated NF-kappaB protects cancer cells against apoptosis, thus blunting SMC3's anticancer activity. Based on our previous observations that the nutrient flavonoid luteolin potently blocks TNF-induced NF-kappaB activation in cancer cells, we investigated if the combination of SMC3 and luteolin would achieve a synergistic anticancer activity. The results show that luteolin had no effect on autocrine TNF but it effectively blocked SMC3-induced nuclear factor kappa B (NF-kappaB) activation and expression of anti-apoptotic NF-kappaB targets. When SMC3 and luteolin were combined in treating cancer cells derived from lung and liver tumors, the activation of TNF-dependent apoptosis was markedly sensitized and a synergistic cytotoxic effect was achieved. In addition, the SMC3 and luteolin co-treatment had marginal effect on immortalized normal human bronchial epithelial cells. The results suggest that combination of SMC3 and luteolin is an effective approach for improving the anticancer value of SMC3, which has implications in cancer prevention and therapy.