Blocking anti‐apoptosis as a strategy for cancer chemotherapy: NF‐κB as a target

Abstract

Critical processes underlying cancers must be better understood to develop strategies for treatment and prevention. A chemotherapeutic strategy is proposed that is based upon re-establishment, with a drug, of nullified programmed cell death (apoptosis) in cancer cells, which to survive have mutated to block apoptosis. A chemotherapy that is specific against tumors implanted in mice demonstrated the feasibility of this principle. This therapy is specific because it affects a process unique to cancer cells. It also has the advantage of killing these cells, in contrast to reversibly blocking their proliferation. The anti-apoptotic transcription factor NF-kappaB provides a potential therapeutic target in estrogen receptor negative (ER-) breast cancers that over-express the epidermal growth factor family of receptors (EGFR). Further investigations of the pathways utilize dominant negative protein inhibitory peptide, and small inhibitory RNAs (siRNAs) to block the production of relevant enzymes.

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

“…16,[22][23][24] These studies suggest that sensitization of cancer cells to apoptosis by inhibiting NF-κB activation may be a promising strategy for cancer treatment. [25][26][27][28] In early work, we and others 29 have shown that H 2 O 2 induces apoptosis in primary hepatocyte culture, but the rat HCC cell line ARL-6, which exhibits constitutive activation of NF-κB, appeared relatively refractory to this type of cell death. 30 We therefore considered that NF-κB may protect HCC cells from cell death induced by oxidative stress.…”

IKK/NF- B signaling: balancing life and death - a new approach to cancer therapy

“…The pivotal role of the IKKβ/NF-κB signaling pathway in inhibition of PCD, tumor promotion, and tumor progression, together with the occurrence of constitutively activated NF-κB in various solid and hematopoietic malignancies, strongly suggests that IKKβ and/or NF-κB inhibitors would be useful in cancer therapy. In fact, much effort is currently invested in developing various IKKβ and/or NF-κB inhibitors and testing their efficacy in both animal models and human cancer (109,110). Many inhibitors currently available are not specific for either IKKβ or NF-κB.…”

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…The pivotal role of the NF-B signaling pathway in apoptosis, tumor promotion and tumor maintenance, strongly suggests that NF-B inhibitors would be useful in cancer therapy, and much efforts is currently invested in developing NF-B inhibitors in cancers (10,14,85,86). Several agents have been implemented to inhibit IKK/NF-B activity, because of the relevance of this process in cancer and those related with inflammation, such as curcumin, ginseng extract, resveratrol, green tea extract have anti-inflammatory and antiproliferative propertiese (87).…”