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MnTnHex-2-PyP⁵⁺ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

ABSTRACT: The manganese(III) porphyrin MnTnHex-2-PyP⁵⁺ (MnTnHex) is a potent superoxide dismutase mimic and modulator of redox-based transcriptional activity that has been studied in the context of different human disease models, including cancer. Nevertheless, for lung cancer, hardly any information is available. Thus, the present work aims to fill this gap and reports the effects of MnTnHex in non-small cell lung cancer (NSCLC) cells, more specifically, A549 and H1975 cells, in vitro. Both cell lines were initially characterized in terms of innate levels of catalase, glutathione peroxidase 1, and peroxiredoxins 1 and 2. To assess the effect of MnTnHex in NSCLC, alone or in combination with cisplatin, endpoints related to the cell viability, cell cycle distribution, cell motility, and characterization of the volatile carbonyl compounds (VCCs) generated in the extracellular medium (i.e., exometabolome) were addressed. The results show that MnTnHex as a single drug markedly reduced the viability of both NSCLC cell lines, with some IC₅₀ values reaching sub-micromolar levels. This redox-active drug also altered the cell cycle distribution, induced cell death, and increased the cytotoxicity pattern of cisplatin. MnTnHex also reduced collective cell migration. Finally, the metabolomics study revealed an increase in the levels of a few VCCs associated with oxidative stress in MnTnHex-treated cells. Altogether these results suggest the therapeutic potential of MnTnHex to be further explored, either alone or in combination therapy with cisplatin, in NSCLC.

SUBMITTER: Soares RB

PROVIDER: S-EPMC9686800 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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MnTnHex-2-PyP<sup>5+</sup> Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

Soares Rita B RB Manguinhas Rita R Costa João G JG Saraiva Nuno N Gil Nuno N Rosell Rafael R Camões Sérgio P SP Batinic-Haberle Ines I Spasojevic Ivan I Castro Matilde M Miranda Joana P JP Amaro Filipa F Pinto Joana J Fernandes Ana S AS Guedes de Pinho Paula P Oliveira Nuno G NG

Antioxidants (Basel, Switzerland) 20221107 11

The manganese(III) porphyrin MnTnHex-2-PyP<sup>5+</sup> (MnTnHex) is a potent superoxide dismutase mimic and modulator of redox-based transcriptional activity that has been studied in the context of different human disease models, including cancer. Nevertheless, for lung cancer, hardly any information is available. Thus, the present work aims to fill this gap and reports the effects of MnTnHex in non-small cell lung cancer (NSCLC) cells, more specifically, A549 and H1975 cells, in vitro. Both ce ...[more]

PMID: 36358570

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Project description:Cisplatin is an extensively used chemotherapeutic drug for lung cancer, but the development of resistance decreases its effectiveness in the treatments of non-small cell lung cancer (NSCLC). In this study, we examined the effects of metformin, a widely used antidiabetic drug, on cisplatin radiosensitization in NSCLC cell lines. Human NSCLC cell lines, A549 (cisplatin-resistant) and H460 (cisplatin-sensitive), were treated with metformin, cisplatin or a combination of both drugs before ionizing radiation. Cell proliferation, clonogenic assays, western blotting, cisplatin-DNA adduct formation and immunocytochemistry were used to characterize the treatments effects. Metformin increased the radiosensitivity of NSCLC cells. Metformin showed additive and over-additive effects in combination with cisplatin and the radiation response in the clonogenic assay in H460 and A549 cell lines (p = 0.018 for the interaction effect between cisplatin and metformin), respectively. At the molecular level, metformin led to a significant increase in cisplatin-DNA adduct formation compared with cisplatin alone (p < 0.01, ANOVA-F test). This was accompanied by a decreased expression of the excision repair cross-complementation 1 expression (ERCC1), a key enzyme in nucleotide excision repair pathway. Furthermore, compared with each treatment alone metformin in combination with cisplatin yielded the lowest level of radiation-induced Rad51 foci, an essential protein of homologous recombination repair. Ionizing radiation-induced γ-H2AX and 53BP1 foci persisted longer in both cell lines in the presence of metformin. Pharmacological inhibition of AMP-activated protein kinase (AMPK) demonstrated that metformin enhances the radiosensitizing effect of cisplatin through an AMPK-dependent pathway only in H460 but not in A549 cells. Our results suggest that metformin can enhance the effect of combined cisplatin and radiotherapy in NSCLC and can sensitize these cells to radiation that are not sensitized by cisplatin alone.

Project description:BackgroundNon-small cell lung cancer (NSCLC), the most prevalent lung cancer subtype, presents significant treatment challenges. Cisplatin (CP)-based regimens are central to the treatment of multiple solid tumors, but its use is restricted due to its dose-related renal toxicity. We previously found that fluorofenidone {1-[3-fluorophenyl]-5-methyl-2-[(1H)]-pyridone (AKF-PD)} effectively reverses CP-induced acute kidney injury (AKI). However, it remains unclear whether AKF-PD can synergistically ameliorate NSCLC when used together with CP. Thus, this study sought to investigate the effect of AKF-PD on NSCLC and examined its combinatory use with CP for cancer treatment.MethodsWe conducted cell viability assays, 5-ethynyl-2'-deoxyuridine (EdU) experiments, colony-forming assays, wound-healing tests, and Transwell experiments in A549 and H1299 cells to explore the effects of AKF-PD on NSCLC. We then detected the epithelial-mesenchymal transition (EMT) markers [i.e., epithelial cadherin (E-cadherin), matrix metallopeptidase 9 (MMP9), vimentin, and snail family transcriptional repressor 1 (SNAIL)], phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK), to identify the potential mechanisms of AKF-PD. Further, via the combined use of AKF-PD and CP, we found that AKF-PD enhanced the antitumor effect of CP, and we suggest that this may be due to its inhibitory effect on EMT. We also examined the effect of combining AKF-PD and CP in other cancer cell lines, including Hela, SiHA, MDA-MB-231, 5-8F, and UM-UC-3 cells.ResultsAKF-PD significantly inhibited the proliferation and invasion of NSCLC cells (A549 and H1299), suppressed the activation of the MAPK and PI3K/AKT/mTOR pathways, and inhibited the EMT of the tumor cells. When AKF-PD was used in combination with CP, these effects were further enhanced. We also found that AKF-PD enhanced the anti-cancer effect of CP in a variety of cancer cell lines, including cervical cancer (Hela cells and SiHA cells), nasopharyngeal cancer (5-8F cells), triple-negative breast cancer (MDA-MB-231 cells), and bladder cancer (UM-UC-3 cells).ConclusionsAKF-PD not only mitigates CP-induced AKI but also enhances the anti-cancer efficacy of CP. Our findings provide valuable insights into the treatment of NSCLC and may have clinical applications.

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MnTnHex-2-PyP⁵⁺ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

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MnTnHex-2-PyP<sup>5+</sup> Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

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MnTnHex-2-PyP5+ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

Publications

MnTnHex-2-PyP<sup>5+</sup> Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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MnTnHex-2-PyP⁵⁺ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.