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SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation.
Biochem Pharmacol. 2008 Dec 01; 76(11):1404-16.BP

Abstract

Because the phosphatidylinositol-3-kinase-AKT pathway is emerging as an important regulator of tumor cell survival, inhibitors of this pathway have enormous potential in cancer treatment. A specific inhibitor of AKT, [d-3-deoxy-2-O-methyl-myo-inositol-1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate]] (SH-5) has been recently synthesized, but little is known about its effects on cytokine signaling. We found that SH-5 potentiated the apoptosis induced by tumor necrosis factor (TNF), as indicated by intracellular esterase staining, annexin V staining, and caspase-3 activation. This effect of SH-5 correlated with downregulation of various gene products that mediate cell survival, proliferation, metastasis, and invasion, all known to be regulated by NF-kappaB. SH-5 also blocked NF-kappaB activation induced by TNF-alpha, lipopolysaccharide, phorbol ester, and cigarette smoke but not that activated by hydrogen peroxide and RANK ligand, indicating differential requirement of AKT. Inhibition of NF-kappaB correlated with abrogation of phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase (IKK). This led to suppression of the phosphorylation and translocation of p65 and also of NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKKbeta but not that induced by p65 transfection. Thus, our results clearly demonstrate that inhibition of AKT leads to potentiation of apoptosis through modulation of NF-kappaB signaling.

Authors+Show Affiliations

Cytokine Research Laboratory, Departments of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18606397

Citation

Sethi, Gautam, et al. "SH-5, an AKT Inhibitor Potentiates Apoptosis and Inhibits Invasion Through the Suppression of Anti-apoptotic, Proliferative and Metastatic Gene Products Regulated By IkappaBalpha Kinase Activation." Biochemical Pharmacology, vol. 76, no. 11, 2008, pp. 1404-16.
Sethi G, Ahn KS, Sung B, et al. SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. Biochem Pharmacol. 2008;76(11):1404-16.
Sethi, G., Ahn, K. S., Sung, B., Kunnumakkara, A. B., Chaturvedi, M. M., & Aggarwal, B. B. (2008). SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. Biochemical Pharmacology, 76(11), 1404-16. https://doi.org/10.1016/j.bcp.2008.05.023
Sethi G, et al. SH-5, an AKT Inhibitor Potentiates Apoptosis and Inhibits Invasion Through the Suppression of Anti-apoptotic, Proliferative and Metastatic Gene Products Regulated By IkappaBalpha Kinase Activation. Biochem Pharmacol. 2008 Dec 1;76(11):1404-16. PubMed PMID: 18606397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. AU - Sethi,Gautam, AU - Ahn,Kwang Seok, AU - Sung,Bokyung, AU - Kunnumakkara,Ajaikumar B, AU - Chaturvedi,Madan M, AU - Aggarwal,Bharat B, Y1 - 2008/07/05/ PY - 2008/03/18/received PY - 2008/05/10/revised PY - 2008/05/16/accepted PY - 2008/7/9/pubmed PY - 2009/1/10/medline PY - 2008/7/9/entrez SP - 1404 EP - 16 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 76 IS - 11 N2 - Because the phosphatidylinositol-3-kinase-AKT pathway is emerging as an important regulator of tumor cell survival, inhibitors of this pathway have enormous potential in cancer treatment. A specific inhibitor of AKT, [d-3-deoxy-2-O-methyl-myo-inositol-1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate]] (SH-5) has been recently synthesized, but little is known about its effects on cytokine signaling. We found that SH-5 potentiated the apoptosis induced by tumor necrosis factor (TNF), as indicated by intracellular esterase staining, annexin V staining, and caspase-3 activation. This effect of SH-5 correlated with downregulation of various gene products that mediate cell survival, proliferation, metastasis, and invasion, all known to be regulated by NF-kappaB. SH-5 also blocked NF-kappaB activation induced by TNF-alpha, lipopolysaccharide, phorbol ester, and cigarette smoke but not that activated by hydrogen peroxide and RANK ligand, indicating differential requirement of AKT. Inhibition of NF-kappaB correlated with abrogation of phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase (IKK). This led to suppression of the phosphorylation and translocation of p65 and also of NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKKbeta but not that induced by p65 transfection. Thus, our results clearly demonstrate that inhibition of AKT leads to potentiation of apoptosis through modulation of NF-kappaB signaling. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/18606397/SH_5_an_AKT_inhibitor_potentiates_apoptosis_and_inhibits_invasion_through_the_suppression_of_anti_apoptotic_proliferative_and_metastatic_gene_products_regulated_by_IkappaBalpha_kinase_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(08)00349-3 DB - PRIME DP - Unbound Medicine ER -