Inhibition of NF-kappaB and proteasome activity in tumors: can we improve the therapeutic potential of topoisomerase I and topoisomerase II poisons.
Activation of signaling pathways following DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. NF-kappaB, 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-kappaB 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 non-small cell lung cancers differed. In this review we will discuss the role of NF-kappaB 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 studies may be useful for translation to a clinical setting for development of more effective therapeutic strategies.
Ganapathi
Ram
R
Taussig Cancer Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. ganapar@cc.ccf.org
Vaziri
Susan A J
SA
Tabata
Masahiro
M
Takigawa
Nagio
N
Grabowski
Dale R
DR
Bukowski
Ronald M
RM
Ganapathi
Mahrukh K
MK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D003546:Cysteine Endopeptidases; D004249:DNA Damage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D046988:Proteasome Endopeptidase Complex; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D016328:NF-kappa B; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex