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. 2019 Aug 15:671:130-142.
doi: 10.1016/j.abb.2019.07.002. Epub 2019 Jul 2.

Development and characterization of a new inhibitor of heme oxygenase activity for cancer treatment

Olga Mucha  1 , Paulina Podkalicka  1 , Maciej Mikulski  2 , Szymon Barwacz  1 , Kalina Andrysiak  1 , Anna Biela  3 , Mateusz Mieczkowski  4 , Neli Kachamakova-Trojanowska  4 , Damian Ryszawy  5 , Arkadiusz Białas  2 , Bożena Szelążek  6 , Przemysław Grudnik  7 , Eliza Majewska  2 , Kinga Michalik  2 , Krzysztof Jakubiec  2 , Marcin Bień  2 , Natalia Witkowska  2 , Karolina Gluza  2 , Dariusz Ekonomiuk  2 , Kamil Sitarz  2 , Michał Gałęzowski  2 , Krzysztof Brzózka  2 , Grzegorz Dubin  6 , Alicja Józkowicz  1 , Józef Dulak  8 , Agnieszka Łoboda  9
Affiliations

Development and characterization of a new inhibitor of heme oxygenase activity for cancer treatment

Olga Mucha et al. Arch Biochem Biophys. .

Abstract

Heme oxygenase-1 (HO-1, HMOX1) degrades pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe2+) 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.

Keywords: Angiogenesis; HO-1; Migration; Pancreatic cancer; Prostate cancer; Tumorigenesis.

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