Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha - PubMed (original) (raw)
Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha
Mei Y Koh et al. Mol Cancer Ther. 2008 Jan.
Abstract
We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1alpha (HIF-1alpha) within the tumor. We now report that PX-478 inhibits HIF-1alpha protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1alpha inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1alpha mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5' untranslated region of HIF-1alpha. Moreover, to a lesser extent, PX-478 also inhibits HIF-1alpha deubiquitination resulting in increased levels of polyubiquitinated HIF-1alpha. The inhibitory effect of PX-478 on HIF-1alpha levels is primarily due to its inhibition of translation because HIF-1alpha translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1alpha at multiple levels that together or individually may contribute to its antitumor activity against HIF-1alpha-expressing tumors.
Similar articles
- Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha.
Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Welsh S, et al. Mol Cancer Ther. 2004 Mar;3(3):233-44. Mol Cancer Ther. 2004. PMID: 15026543 - Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer.
Schwartz DL, Bankson JA, Lemos R Jr, Lai SY, Thittai AK, He Y, Hostetter G, Demeure MJ, Von Hoff DD, Powis G. Schwartz DL, et al. Mol Cancer Ther. 2010 Jul;9(7):2057-67. doi: 10.1158/1535-7163.MCT-09-0768. Epub 2010 Jun 29. Mol Cancer Ther. 2010. PMID: 20587661 Free PMC article. - PX-478, an inhibitor of hypoxia-inducible factor-1alpha, enhances radiosensitivity of prostate carcinoma cells.
Palayoor ST, Mitchell JB, Cerna D, Degraff W, John-Aryankalayil M, Coleman CN. Palayoor ST, et al. Int J Cancer. 2008 Nov 15;123(10):2430-7. doi: 10.1002/ijc.23807. Int J Cancer. 2008. PMID: 18729192 Free PMC article. - A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor.
Lee K, Kim HM. Lee K, et al. Arch Pharm Res. 2011 Oct;34(10):1583-5. doi: 10.1007/s12272-011-1021-3. Arch Pharm Res. 2011. PMID: 22076756 Review. - HIF-1alpha and cancer therapy.
Koh MY, Spivak-Kroizman TR, Powis G. Koh MY, et al. Recent Results Cancer Res. 2010;180:15-34. doi: 10.1007/978-3-540-78281-0_3. Recent Results Cancer Res. 2010. PMID: 20033376 Review.
Cited by
- Targeting PLOD2 suppresses invasion and metastatic potential in radiorecurrent prostate cancer.
Frame G, Leong H, Haas R, Huang X, Wright J, Emmenegger U, Downes M, Boutros PC, Kislinger T, Liu SK. Frame G, et al. BJC Rep. 2024;2(1):60. doi: 10.1038/s44276-024-00085-3. Epub 2024 Aug 21. BJC Rep. 2024. PMID: 39184453 Free PMC article. - Identification of small-molecule ligand-binding sites on and in the ARNT PAS-B domain.
Xu X, Closson JD, Marcelino LP, Favaro DC, Silvestrini ML, Solazzo R, Chong LT, Gardner KH. Xu X, et al. J Biol Chem. 2024 Sep;300(9):107606. doi: 10.1016/j.jbc.2024.107606. Epub 2024 Jul 24. J Biol Chem. 2024. PMID: 39059491 Free PMC article. - Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation.
Yang JX, Chuang YC, Tseng JC, Liu YL, Lai CY, Lee AY, Huang CF, Hong YR, Chuang TH. Yang JX, et al. J Exp Clin Cancer Res. 2024 Jun 17;43(1):169. doi: 10.1186/s13046-024-03094-9. J Exp Clin Cancer Res. 2024. PMID: 38880883 Free PMC article. - HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.
Nakamura A, Jo S, Nakamura S, Aparnathi MK, Boroojeni SF, Korshko M, Park YS, Gupta H, Vijayan S, Rockel JS, Kapoor M, Jurisica I, Kim TH, Haroon N. Nakamura A, et al. Cell Mol Immunol. 2024 Jul;21(7):770-786. doi: 10.1038/s41423-024-01183-5. Epub 2024 Jun 5. Cell Mol Immunol. 2024. PMID: 38839914 - Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.
Trejo-Solís C, Castillo-Rodríguez RA, Serrano-García N, Silva-Adaya D, Vargas-Cruz S, Chávez-Cortéz EG, Gallardo-Pérez JC, Zavala-Vega S, Cruz-Salgado A, Magaña-Maldonado R. Trejo-Solís C, et al. Metabolites. 2024 Apr 25;14(5):249. doi: 10.3390/metabo14050249. Metabolites. 2024. PMID: 38786726 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous