6EHA

Heme oxygenase 1 in complex with inhibitor

6EHA の概要

• エントリーDOI: 10.2210/pdb6eha/pdb
• 分子名称: Heme oxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 1-(3-imidazol-1-ylpropyl)-5-(2-methylpropyl)-4-phenyl-imidazole, ... (4 entities in total)
• 機能のキーワード: heme oxygenase, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67570.93

構造登録者

Grudnik, P.,Mieczkowski, M. (登録日: 2017-09-12, 公開日: 2018-10-10, 最終更新日: 2024-05-08)

主引用文献

Mucha, O.,Podkalicka, P.,Mikulski, M.,Barwacz, S.,Andrysiak, K.,Biela, A.,Mieczkowski, M.,Kachamakova-Trojanowska, N.,Ryszawy, D.,Bialas, A.,Szelazek, B.,Grudnik, P.,Majewska, E.,Michalik, K.,Jakubiec, K.,Bien, M.,Witkowska, N.,Gluza, K.,Ekonomiuk, D.,Sitarz, K.,Galezowski, M.,Brzozka, K.,Dubin, G.,Jozkowicz, A.,Dulak, J.,Loboda, A.
Development and characterization of a new inhibitor of heme oxygenase activity for cancer treatment.
Arch.Biochem.Biophys., 671:130-142, 2019

PubMed Abstract: Heme oxygenase-1 (HO-1, HMOX1) degrades pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe) and biliverdin. The enzyme exerts multiple cytoprotective functions associated with the promotion of angiogenesis and counteraction of the detrimental effects of cellular stress which are crucial for the survival of both normal and tumor cells. Accordingly, in many tumor types, high expression of HO-1 correlates with poor prognosis and resistance to treatment, i.e. chemotherapy, suggesting inhibition of HO-1 as a possible antitumor approach. At the same time, the lack of selective and well-profiled inhibitors of HO-1 determines the unmet need for new modulators of this enzyme, with the potential to be used in either adjuvant therapy or as the stand-alone targeted therapeutics. In the current study, we provided novel inhibitors of HO-1 and validated the effect of pharmacological inhibition of HO activity by the imidazole-based inhibitor (SLV-11199) in human pancreatic (PANC-1) and prostate (DU-145) cancer cell lines. We demonstrated potent inhibition of HO activity in vitro and showed associated anticancer effectiveness of SLV-11199. Treatment with the tested compound led to decreased cancer cell viability and clonogenic potential. It has also sensitized the cancer cells to chemotherapy. In PANC-1 cells, diminished HO activity resulted in down-regulation of pro-angiogenic factors like IL-8. Mechanistic investigations revealed that the treatment with SLV-11199 decreased cell migration and inhibited MMP-1 and MMP-9 expression. Moreover, it affected mesenchymal phenotype by regulating key modulators of the epithelial to mesenchymal transition (EMT) signalling axis. Finally, F-actin cytoskeleton and focal contacts were destabilized by the reported compound. Overall, the current study suggests a possible relevance of the tested novel inhibitor of HO activity as a potential anticancer compound. To support such utility, further investigation is still needed, especially in in vivo conditions.

PubMed: 31276659
DOI: 10.1016/j.abb.2019.07.002

実験手法

X-RAY DIFFRACTION (2 Å)