Pirfenidone Sensitizes NCI-H460 Non-Small Cell Lung Cancer Cells to Paclitaxel and to a Combination of Paclitaxel with Carboplatin

Branco, Helena; Oliveira, Júlio Fernando Pinto; Antunes, Catarina; Santos, Lúcio Lara; Vasconcelos, M. Helena; Xavier, Cristina P.R.

doi:10.3390/ijms23073631

Cited by 16 publications

(19 citation statements)

References 47 publications

(76 reference statements)

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“…IPF drugs are associated with the development of anti-tumor drugs such as nintedanib, an oral small molecule tyrosine kinase inhibitor initially developed for lung cancer and approved for the treatment of IPF. Pirfenidone has a sensitizing effect on the combination of paclitaxel and carboplatin used in clinical practice ( Branco et al, 2022 ). We believe that the identification of related anti-tumor drugs has potential significance for IPF treatment.…”

Section: Resultsmentioning

confidence: 99%

Genes related to N6-methyladenosine in the diagnosis and prognosis of idiopathic pulmonary fibrosis

Zhang

Wang

et al. 2023

Front. Genet.

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Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary fibrotic disease with unknown etiology and poor outcomes. It severely affects the quality of life. In this study, we comprehensively analyzed the expression of N6-methyladenosine (m6A) RNA methylation regulators using gene expression data from various tissue sources in IPF patients and healthy volunteers.Methods: The gene expression matrix and clinical characteristics of IPF patients were retrieved from the Gene Expression Omnibus database. A random forest model was used to construct diagnosis signature m6A regulators. Regression analysis and correlation analysis were used to identify prognosis m6A regulators. Consensus cluster analysis was used to construct different m6A prognosis risk groups, then functional enrichment, immune infiltration and drug sensitivity analysis were performed.Result: Five candidate m6A genes from lung tissue were used to predict the incidence, and the incidence was validated using datasets from bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells. Subsequently, the BALF dataset containing outcomes data was used for the prognosis analysis of m6A regulators. METTL14, G3BP2, and ZC3H13 were independent protective factors. Using correlation analysis with lung function in the lung tissue-derived dataset, METTL14 was a protective factor in IPF. Based on METTL14 and G3BP2, a consensus cluster analysis was applied to distinguish the prognostic m6A regulation patterns. The low-risk group’s prognosis was significantly better than the high-risk group. Biological processes regulated by various risk groups included fibrogenesis and cell adhesion. Analysis of immune cell infiltration showed upregulation of neutrophils in the m6A high-risk group. Subsequently, five m6A high-risk group sensitive drugs and one m6A low-risk group sensitive drug were identified.Discussion: These findings suggest that m6A regulators are involved in the diagnosis and prognosis of IPF, and m6A patterns are a method to identify IPF outcomes.

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Section: Resultsmentioning

confidence: 99%

Genes related to N6-methyladenosine in the diagnosis and prognosis of idiopathic pulmonary fibrosis

Zhang

Wang

et al. 2023

Front. Genet.

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“…Therefore, novel therapeutic targets are required to provide these patients with enhanced treatment options. [ 55 ]. In this scenario, the use of dual target therapy using an αv𝛽6 integrin ligand conjugated with RTKI may assume a fundamental role.…”

Section: Discussionmentioning

confidence: 99%

Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer

Andreucci

Bugatti

Peppicelli

et al. 2023

IJMS

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Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGFβ is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.

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“…In other tumoral contexts, some reports have been made in combining Paclitaxel with different repurposing agents, e.g., Duarte et al demonstrated that antimalarial drugs, such as Chloroquine, Artesunate and Mefloquine, could act synergistically with Paclitaxel for breast cancer therapy [ 31 , 32 ]. More recently, Branco et al demonstrate that Pirfenidone, an antifibrotic drug, sensitizes non-small cell lung cancer cells to Paclitaxel [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma

Nunes

Duarte

Vale

et al. 2022

Cancers

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Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou–Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.

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Pirfenidone Sensitizes NCI-H460 Non-Small Cell Lung Cancer Cells to Paclitaxel and to a Combination of Paclitaxel with Carboplatin

Cited by 16 publications

References 47 publications

Genes related to N6-methyladenosine in the diagnosis and prognosis of idiopathic pulmonary fibrosis

Genes related to N6-methyladenosine in the diagnosis and prognosis of idiopathic pulmonary fibrosis

Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer

Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma

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