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

Mucha, Olga; Podkalicka, Paulina; Mikulski, Maciej; Barwacz, Szymon; Andrysiak, Kalina; Biela, Anna; Mieczkowski, Mateusz; Kachamakova‐Trojanowska, Neli; Ryszawy, Damian; Białas, Arkadiusz; Szelążek, Bożena; Grudnik, P.; Majewska, Eliza; Michalik, Kinga; Jakubiec, K.; Bień, Marcin; Witkowska, Natalia; Gluza, Karolina; Ekonomiuk, Dariusz; Sitarz, Kamil S.; Gałęzowski, Michał; Brzózka, Krzysztof; Dubin, Grzegorz; Józkowicz, Alicja; Dulak, Józef; Łoboda, Agnieszka

doi:10.1016/j.abb.2019.07.002

Cited by 26 publications

(23 citation statements)

References 56 publications

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“…Nonetheless, at the same time, ZnPPIX significantly upregulated HO-1 mRNA level. This is consistent with previously published reports indicating this stimulatory effect on HMOX1 expression what may be, at least in some conditions, a serious drawback [15,19,23]. However, we evaluated the effect of ZnPPIX on the viability of other FH-deficient cell lines and in UOK 268 cells the results were comparable to UOK 262.…”

Section: Discussionsupporting

confidence: 91%

“…Specifically, we aimed at the verification of the synthetic lethality concept of HMOX1 and FH in three different HLRCC cell lines using not only genetic but also pharmacological inhibition of HMOX1. We were especially interested in checking the effectiveness of SLV-11999 inhibitor, described by us recently as the anti-cancer compound in pancreatic and prostate cancer cell lines [23]. We have demonstrated that both strategies hamper cancer cell viability and self-renewal capacity and confirmed that the concept of synthetically lethal interactions of HMOX1 and FH genes might be an attractive option for the treatment of HLRCC-associated tumors.…”

Section: Introductionmentioning

confidence: 76%

“…We have previously shown that HO-1 is essential for proliferation, angiogenesis, and metastasis of different tumor types, including melanoma, rhabdomyosarcoma, and pancreatic cancer [23,33,34]. Of importance, in the study done by Frezza et al, inhibition of HMOX1 was reported to be synthetically lethal for FH-deficient mouse kidney cells [16].…”

Section: Discussionmentioning

confidence: 99%

“…For pharmacological inhibitions various compounds were tested. SLV-11199 (IC 50 = 2.23 ± 0.35 µM for HO-1 and IC 50 = 1.07 µM for HO-2) [23] and QC-308 (IC 50 = 1.25 ± 0.049 µM for HO-1 and IC50 = 1.12 ± 0.028 µM for HO-2, unpublished data) were synthesized as previously described [23]. SnPPIX (IC50 = 0.47 µM for HO-1 and IC50 = 0.18 µM for HO-2), and ZnPPIX (IC50 = 5.45 µM for HO-1 and IC 50 = 2.65 µM for HO-2) [25] were purchased from Frontier Scientific (Logan UT, USA).…”

Section: Drugs and Reagentsmentioning

confidence: 99%

“…It is especially important as HO-2 isoform, on the contrary to the inducible HO-1 is constitutively expressed and is responsible for the maintenance of cellular homeostasis and for example the viability of endothelial cells [20][21][22]. To overcome these problems we [23] and others [24] have recently elaborated on the new, imidazole-based compounds exerting some properties superior to known inhibitors of HO activity.…”

Section: Introductionmentioning

confidence: 99%

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Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

et al. 2020

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Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)—an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Drugs and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

et al. 2020

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Nano‐sized Co(II), Ni(II), and Zr(IV) complexes of quinaldine‐based azo dye for promising therapeutic and catalytic applications: Synthesis, characterization, density functional theory studies and molecular docking

Khedr,

Gaber,

Elsharkawy

et al. 2023

Applied Organom Chemis

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Novel azo dye containing the heterocyclic quinaldine nucleus, 3‐((2‐methylquinolin‐4‐yl)diazenyl)naphthalen‐2‐ol HL, and its Co(II), Ni(II) and Zr(IV) nano‐sized metal chelates have been synthesized and fully characterized by alternative analytical and spectral techniques. The finding indicated that the ligand coordinated as a monobasic bidentate via azo nitrogen and hydroxyl oxygen atom, resulting in octahedral geometry towards Co(II) and Zr(IV) complexes, and square planer geometry towards Ni(II) metal ion. Theoretical studies by DFT/B3LYP/6‐311+G(d,p)/LANLDZ including energetic parameters, geometrical optimization, dipole moment, and HOMO–LUMO energy gap were applied to support the geometrical arrangement of the complexes. The produced complexes were generated at the nanoscale, as evidenced by the average particle size from TEM. The average particle size calculated from TEM images for Co(II), Ni(II), and Zr(IV) complexes is 6.0, 12.0, and 5.5 nm, respectively. The antibacterial activity of the ligand compared with its metal complexes shows enhanced activity over the metal complexes against different types of bacteria. Antitumor efficacy of the compounds was tested against A‐549 and PANC‐1 cells, compared with the vinblastine standard. The cytotoxic efficiency of both Co(II) and Ni(II) complexes exceeded that of vinblastine. The anticancer activity of the Zr complex was then studied using molecular docking to determine the interactions between this molecule and PANC‐1. Docking studies revealed that the Zr complex produces four hydrogen bond contacts with the active amino acid residues Arg 136 and Asp 140, two hydrophobic interactions with Val 50 and Leu 147, and two electrostatic interactions with Arg 136. Also, the catalytic property of the free ligand and nanocomplexes were tested on the oxidative degradation of methyl violet 2B dye in the presence of H2O2. The following arrangement was observed for the pseudo‐first‐order rate constants: Co(II) complex (0.068 min−1) > Ni(II) complex (0.066 min−1) > Zr(IV) complex (0.061 min−1) > HL (0.037 min−1).

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Computational Designing and Prediction of ADMET Properties of Four Novel Imidazole‐based Drug Candidates Inhibiting Heme Oxygenase‐1 Causing Cancers

Rahman

Talukder

Akter

2021

Molecular Informatics

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The overexpression of heme oxygenase-1 (HO-1) contributes to the development of several types of cancers. The inhibition of HO-1 through imidazole-based drugs, which is non-competitive with heme, is a focus of anticancer drug research. We designed the four following novel HO-1 inhibiting compounds:. All compounds showed a strong binding affinity with HO-1 in molecular docking studies. The in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) data showed that the compounds would be available orally in an acceptable manner. The bioactivity scores revealed that they were moderately active substances. They were found as non-mutagen, non-tumorigenic, non-irritant, and non-detrimental to the reproductive system. Finally, the drug-likeness values of the compounds were obtained as À 0.71, À 1.64, À 2.04, and 0.4 respectively, with the final drug-score of 0.60, 0.54, 0.51, and 0.77 respectively.

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

Cited by 26 publications

References 56 publications

Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

Nano‐sized Co(II), Ni(II), and Zr(IV) complexes of quinaldine‐based azo dye for promising therapeutic and catalytic applications: Synthesis, characterization, density functional theory studies and molecular docking

Computational Designing and Prediction of ADMET Properties of Four Novel Imidazole‐based Drug Candidates Inhibiting Heme Oxygenase‐1 Causing Cancers

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