Metal-Based Anticancer Complexes and p53: How Much Do We Know?

Alfadul, Samah Mutasim; Matnurov, E.M.; Varakutin, Alexander E.; Babak, Maria V.

doi:10.3390/cancers15102834

Cancers

2023

DOI: 10.3390/cancers15102834

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Metal-Based Anticancer Complexes and p53: How Much Do We Know?

Samah Mutasim Alfadul

E.M. Matnurov

Alexander E. Varakutin

et al.

Abstract: P53 plays a key role in protecting the human genome from DNA-related mutations; however, it is one of the most frequently mutated genes in cancer. The P53 family members p63 and p73 were also shown to play important roles in cancer development and progression. Currently, there are various organic molecules from different structural classes of compounds that could reactivate the function of wild-type p53, degrade or inhibit mutant p53, etc. It was shown that: (1) the function of the wild-type p53 protein was de… Show more

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2024

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Cited by 3 publications

References 167 publications

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Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells

Xhafa,

Di Nicola,

Tombesi

et al. 2024

J. Med. Chem.

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The synthesis and characterization of nine Schiff bases of pyrazolone ligands HL n (n = 1–9) and the corresponding zinc(II) complexes 1–9 of composition [Zn(L n )2] (n = 1–9) are reported. The molecular structures of complexes 2, 3, 4, 8, and 9 were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the HL n ligands and the derived complexes. A mechanism of dissociation and hydrolyzation of the coordinated Schiff base ligands is suggested, confirmed experimentally by powder X-ray diffraction study and photophysical studies. Complexes 1–9 were investigated in vitro as anticancer agents, along with mutant p53 (mutp53) protein levels in human cancer cell lines carrying R175H and R273H mutp53 proteins. Only those complexes with the highest Zn(II) ion release via dissociation have shown a significant cytotoxic activity with reduction of mutp53 protein levels.

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Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells

Xhafa,

Di Nicola,

Tombesi

et al. 2024

J. Med. Chem.

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Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease

Hao,

Lin,

Kong

et al. 2024

Open Medicine

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Background This study investigated the role and mechanisms of cullin-1 (CUL1) in chronic obstructive pulmonary disease (COPD). Methods Cigarette smoke extract (CSE)-treated mouse pulmonary microvascular endothelial cells (mPMECs) and cigarette smoke inhalation (CSI)-stimulated mice were used to construct in vitro and in vivo COPD models, respectively. CUL1 expression was assessed using reverse transcriptase-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to detect cell viability and apoptosis, respectively. We conducted an enzyme-linked immunosorbent assay on mPMECs and bronchoalveolar lavage fluid (BALF) to detect inflammatory factors. Reactive oxygen species, malondialdehyde, and superoxide dismutase were detected using the corresponding kits. The histological characteristics of the lung tissues were determined by hematoxylin and eosin staining. Results CUL1 expression was downregulated in COPD. CUL1 overexpression significantly promoted cell viability, reduced cell apoptosis, and inhibited inflammatory responses and oxidative stress in CSE-treated mPMECs. These changes were reversed by the p53 agonist nutlin-3. In addition, CUL1 overexpression significantly relieved COPD in mice, as confirmed by the reduced secretion of inflammatory factors in BALF, inhibited oxidative stress response, and improved lung function. Conclusion CUL1 plays a protective role in CSE-treated mPMECs and CSI-stimulated mice by inhibiting the p53 signaling pathway.

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Bioinformatic Characterization of the Functional and Structural Effect of Single Nucleotide Mutations in Patients with High-Grade Glioma

Vélez Gómez,

Martínez Garro,

Ortiz Gómez

et al. 2024

Biomedicines

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Background: Gliomas are neoplasms of the central nervous system that originate in glial cells. The genetic characteristics of this type of neoplasm are the loss of function of tumor suppressor genes such as TP53 and somatic mutations in genes such as IDH1/2. Additionally, in clinical cases, de novo single nucleotide polymorphisms (SNP) are reported, of which their pathogenicity and their effects on the function and stability of the protein are known. Methodology: Non-synonymous SNPs were analyzed for their structural and functional effect on proteins using a set of bioinformatics tools such as SIFT, PolyPhen-2, PhD-SNP, I-Mutant 3.0, MUpro, and mutation3D. A structural comparison between normal and mutated residues for disease-associated coding SNPs was performed using TM-aling and the SWISS MODEL. Results: A total of 13 SNPs were obtained for the TP53 gene, 1 SNP for IDH1, and 1 for IDH2, which would be functionally detrimental and associated with disease. Additionally, these changes compromise the structure and function of the protein; the A161S SNP for TP53 that has not been reported in any databases was classified as detrimental. Conclusions: All non-synonymous SNPs reported for TP53 were in the region of the deoxyribonucleic acid (DNA) binding domain and had a great impact on the function and stability of the protein. In addition, the two polymorphisms detected in IDH1 and IDH2 genes compromise the structure and activity of the protein. Both genes are related to the development of high-grade gliomas. All the data obtained in this study must be validated through experimental approaches.

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Metal-Based Anticancer Complexes and p53: How Much Do We Know?

Cited by 3 publications

References 167 publications

Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells

Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells

Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease

Bioinformatic Characterization of the Functional and Structural Effect of Single Nucleotide Mutations in Patients with High-Grade Glioma

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