Inhibition of mycobacteria proliferation in macrophages by low cisplatin concentration through phosphorylated p53-related apoptosis pathway.

Abstract

BACKGROUND:

Drug resistance is a prominent problem in the treatment of tuberculosis, so it is urgent to develop new anti- tuberculosis drugs. Here, we investigated the effects and mechanisms of cisplatin (DDP) on intracellular Mycobacterium smegmatis to tap the therapeutic potential of DDP in mycobacterial infection.

RESULTS:

Macrophages infected with Mycobacterium smegmatis were treated with DDP alone or combined with isoniazid or rifampicin. The results showed that the bacterial count in macrophages decreased significantly after DDP (≤ 6 μg/mL) treatment. When isoniazid or rifampicin was combined with DDP, the number of intracellular mycobacteria was also significantly lower than that of isoniazid or rifampicin alone. Apoptosis of infected cells increased after 24 h of DDP treatment, as shown by flow cytometry and transmission electron microscopy detection. Transcriptome sequencing showed that there were 1161 upregulated and 645 downregulated differentially expressed genes (DEGs) between the control group and DDP treatment group. A Trp53-centered protein interaction network was found based on the top 100 significant DEGs through STRING and Cytoscape software. The expression of phosphorylated p53, Bax, JAK, p38 MAPK and PI3K increased after DDP treatment, as shown by Western blot analysis. Inhibitors of JAK, PI3K or p38 MAPK inhibited the increase in cell apoptosis and the reduction in the intracellular bacterial count induced by DDP. The p53 promoter Kevetrin hydrochloride scavenges intracellular mycobacteria. If combined with DDP, Kevetrin hydrochloride could increase the effect of DDP on the elimination of intracellular mycobacteria. In conclusion, DDP at low concentrations could activate the JAK, p38 MAPK and PI3K pathways in infected macrophages, promote the phosphorylation of p53 protein, and increase the ratio of Bax to Bcl-2, leading to cell apoptosis, thus eliminating intracellular bacteria and reducing the spread of mycobacteria.

CONCLUSION:

DDP may be a new host-directed therapy for tuberculosis treatment, as well as the p53 promoter Kevetrin hydrochloride.

• Authors: Jiajia Bao, Yonglin He, Chun Yang, Nan Lu, Anlong Li, Sijia Gao, Felycia Fernanda Hosyanto, Jialing Tang, Junzhuo Si, Xia Tang, Huichao Fu, Lei Xu
• Journal: PloS one (PLoS One) Vol. 18 Issue 1 Pg. e0281170 ( 2023) ISSN: 1932-6203 [Electronic] United States
• PMID: 36719870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright: © 2023 Bao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Chemical References

• bcl-2-Associated X Protein
• Cisplatin
• Isoniazid
• Phosphatidylinositol 3-Kinases
• Rifampin
• Tumor Suppressor Protein p53
• Antitubercular Agents
• Nitriles
• Thiourea
• Butanones

Topics

• Apoptosis (drug effects)
• bcl-2-Associated X Protein
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Isoniazid (pharmacology)
• Phosphatidylinositol 3-Kinases
• Rifampin (pharmacology)
• Tumor Suppressor Protein p53 (genetics)
• Antitubercular Agents (pharmacology)
• Drug Resistance, Bacterial (genetics)
• Mycobacterium smegmatis (drug effects, genetics, immunology)
• Macrophages (drug effects, immunology, microbiology)
• Nitriles (pharmacology)
• Thiourea (analogs & derivatives, pharmacology)
• Butanones (pharmacology)