Targeting NF- B activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

“…A decrease in the transcription of several antiapoptotic NF-kB target genes such as Bcl-xl, survivin, and to a lesser extent c-IAP1 and c-IAP2 was observed which could reflect an overall decrease in survival influences preceding caspase activation. AS602868 has been previously shown to induce apoptosis of human acute myeloid leukaemia cells (Frelin et al, 2005), effects that were associated with disruption of the mitochondrial potential and by activation of pro-caspases 9 and 3. It has been demonstrated that p65 siRNA enhanced CPT-11-mediated apoptosis by increasing caspase 3 activity and lowering c-IAP 1 and c-IAP 2 protein levels (Guo et al, 2004).…”

“…In haematopoietic malignancies, inhibition of abnormal constitutive NF-kB activity frequently results in the death of leukaemic cells (Frelin et al, 2005;Garcia et al, 2005). In solid tumours like CRC, however, a combined therapy with antineoplastic drugs appears necessary to get similar results.…”

“…We used a pharmacological inhibitor of the IKK2 kinase (AS602868) that was previously shown to reveal the apoptotic potential of TNF-a in Jurkat cells (Frelin et al, 2003) and to induced apoptosis of primary human acute myeloid leukaemia cells (Frelin et al, 2005). We show that both in vitro and in vivo in HT-29 colon s.c. xenografts AS602868 potentiated antitumour CPT-11 effectiveness by increasing CPT-11-induced apoptosis of HT-29 tumour cells.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…The IKK inhibitors BAY 11-7082 and AS602868 have shown efficacy in leukemia models via their ability to induce increased apoptosis (Frelin et al, 2005;Garcia et al, 2005). Another small-molecule inhibitor of IKK (PS-1145) was found to be selectively toxic for subtypes of diffuse large B-cell lymphoma cells that are associated with NF-kB activation (Lam et al, 2005).…”

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…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). Proteosome inhibitors regulates the degradation of IB and hence inhibits NFB, and a few publications have documented their efficacy in triggering apoptosis in cancer cell lines in combination with either chemotherapeiutic drugs or death-inducing cytokines (88)(89)(90). Sulfasalazine and methotrexate are widely used for treatment of acute states of IBD by inhibiting NF-B activation (91,92), thus, may also decrease the risk of developing cancer.…”