Inhibition of NF-κB and Proteasome Activity in Tumors: Can We Improve the Therapeutic Potential of Topoisomerase I and Topoisomerase II Poisons

Ram      Ganapathi; Susan   A.J.   Vaziri; Masahiro      Tabata; Nagio      Takigawa; Dale   R.   Grabowski; Ronald   M.   Bukowski; Mahrukh   K.   Ganapathi

Abstract

Activation of signaling pathways following DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. NF-κB, a major regulator of the stress response and a negative regulator of apoptosis is often activated following treatment with topoisomerase poisons. Since activation of NF-κB is generally considered to relay an anti-apoptotic signal, inactivation of this signaling molecule is considered to represent an important strategy to improve therapeutic efficacy. Although this strategy seems to be effective in some model systems, our results in human nonsmall cell lung cancers differed. In this review we will discuss the role of NF-κB in mediating topoisomerase poison-induced DNA damage and apoptosis and the consequence of inhibiting its activity. Newer insights about the importance of proteasome inhibitors and anti-apoptotic genes in topoisomerase poison-induced signaling mechanisms leading to apoptosis will also be reviewed. The knowledge obtained from these studi es may be useful for translation to a clinical setting for development of more effective therapeutic strategies.

Keywords: Proteasome, Topoisomerase I