Frontiers in Pharmacology

Our medical research library holds 19 studies published in Frontiers in Pharmacology (2014–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 18 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Frontiers Media]
• Published: 2010 to the present, Switzerland
• Language: English
• ISSN: 1663-9812 (electronic)
• Its record in the NLM Catalog

2020s

• Immune-related gene risk model establishment and role of key gene FUCA1 in malignant pleural mesothelioma. L. Shi, D. Yuan, F. Zhu, et al. 2025;16:1577232. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a rare type of tumor closely associated with asbestos exposure. Increasing evidence shows that high immuno-heterogeneity reduces the therapeutic efficacy of MPM. At present, good biomarkers to screen immunodominant populations and predict the efficacy of immunotherapy are lacking.

  Methods: In this study, expression data from TCGA, GSE2459, GSE51024, and GSE29354 were integrated for model construction. An eight-gene risk score model (FLI1, IL32, FUCA1, CCR2, PSMB10, CCL5, WT1, and KRT5) was constructed using CIBERSORT, weighted gene co-expression network analysis, Cox regression analysis, differentially expressed gene analysis, and protein-protein interaction network. The K-M survival analysis was used to evaluate the prediction ability of the risk score model. The TIDE database and Oncology Drug Sensitivity Genomics database were used to assess the predictive power of risk score models for treatment. In addition, the expression of the key gene in para-carcinoma tissue and MPM samples were detected by Immunohistochemistry. Patient clinical information was employed to evaluate the relationship between key genes and patient survival. Finally, the biological functions of the key gene were examined by in vitro and in vivo experiments.

  Results: The score model was used to divide patients with MPM into low- and high-risk groups. The high-risk group was characterized by a survival disadvantage, and they were less sensitive to immunotherapy. Clinical data suggest that FUCA1, which is a key gene in the model, is an independent risk factor for predicting the prognosis of patients with MPM. A series of experiments demonstrated that FUCA1 expression was negatively correlated with the proliferation, invasion and migration abilities of MPM cells. Further studies revealed that FUCA1 inhibited epithelial-mesenchymal transition in MPM cells by regulating the PI3K-AKT signaling pathway.

  Conclusion: The risk score model provides a new perspective for screening potential populations to benefit from immunotherapy and predicting their survival. FUCA1 may be a potential prognostic biomarker and promising therapeutic target for patients with MPM.

  Copyright © 2025 Shi, Yuan, Zhu, He, Zuo, Chen, Luo, Wang, Huang, Chen and Guo.

• Cost-effectiveness analysis of pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in the Chinese healthcare system. W. Lang, Y. He, C. Hou, et al. 2024;15:1402423. PubMed · Publisher · Free full text

  Abstract

  Objective: The combination of pembrolizumab and chemotherapy has demonstrated notable clinical advantages in improving overall survival than chemotherapy alone for patients with untreated advanced pleural mesothelioma. The purpose of this study was to assess its cost-effectiveness.

  Materials And Methods: A Markov state-transition model was constructed using data from the IND227 phase 3 randomized clinical trial. Utility values for health states were taken from the IND227 trial, and direct medical costs were from the pertinent literature and local pricing data. Outcomes measured included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB). To manage the uncertainty in the model, both probabilistic sensitivity analysis (PSA) and one-way sensitivity analysis (OWSA) were used.

  Results: In the base-case analysis, pembrolizumab plus chemotherapy resulted in an incremental gain of 0.23 QALYs at an additional cost of $18,199.63, resulting in an ICER of $80,557.23/QALY. This was not favorable compared to China's willingness-to-pay (WTP) threshold of $38,042.49/QALY, with an INHB of -0.25 QALYs and an INMB of $-9,605.00. Subgroup analyses showed ICERs for pembrolizumab plus chemotherapy versus chemotherapy of $33,917.61 and $99,536.73 in non-epithelioid and epithelioid patients, respectively. PSA indicated probabilities of cost-effectiveness for pembrolizumab plus chemotherapy at 0.55%, 69.41%, and 0.14% for the entire population and the non-epithelioid and epithelioid subgroups, respectively.

  Conclusion: In the Chinese healthcare system, the combination of pembrolizumab and chemotherapy did not prove to be more cost-effective than chemotherapy alone as an initial treatment for untreated advanced pleural mesothelioma, with the exception of patients who have non-epithelioid histology.

  Copyright © 2025 Lang, He, Hou, Li, Jiang and Mei.

• The association between aspirin use and immune-related adverse events in specific cancer patients receiving ICIs therapy: analysis of the FAERS database. H. Yang, Z. Liu, R. Li, et al. 2023;14:1259628. PubMed · Publisher · Free full text

  Abstract

  Background: The promise of immune checkpoint inhibitors (ICIs) therapy in cancer treatment is tempered by the occurrence of immune-related adverse events (irAEs). Many patients undergoing ICIs also take aspirin, but the association between aspirin and irAEs is not well understood. Methods: This study analyzed adverse reaction data associated with the use of ICIs in the US Food and Drug Administration (FDA) Adverse Event Reporting System FDA Adverse Event Reporting System database, from the approval date of each drug until 1 October 2022. Multivariate logistic regression was employed to assess the association of aspirin use with irAEs in patients receiving ICIs. Results: The results indicated that aspirin use was associated with an increased risk of irAEs in a pan-cancer analysis, with a more pronounced association in specific cancer types such as lung cancer, mesothelioma, and pancreatic cancer. However, in lymphoma, aspirin use was associated with a reduced risk of irAEs. Furthermore, aspirin use was associated with an increased risk of certain irAEs, such as anemia, colitis, myocarditis, myositis, pancreatitis, pericarditis, and pneumonia, while it was associated with a reduced risk of rash, Stevens-Johnson syndrome, and thyroiditis. Conclusion: This study has unveiled an association between aspirin use and irAEs in cancer patients receiving ICIs therapy, emphasizing the need for individualized consideration of patients' medication history when devising cancer treatment plans to enhance efficacy and reduce risks.

  Copyright © 2023 Yang, Liu, Li, Huang and Peng.

• Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies. D.L. Pouliquen, A. Boissard, C. Henry, et al. 2022;13:934534. Review PubMed · Publisher · Free full text

  Abstract

  Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host's immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

  Copyright © 2022 Pouliquen, Boissard, Henry, Coqueret and Guette.

• Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo. S.K. Lam, S. Yan, J.S. Lam, et al. 2022;13:1020343. PubMed · Publisher · Free full text

  Abstract

  Background: Inhalation of asbestos fibers is the most common cause of malignant pleural mesothelioma (MPM). In 2004, the United States Food and Drug Administration approved a combination of cisplatin with pemetrexed to treat unresectable MPM. Nonetheless novel treatment is urgently needed. The objective of this study is to report the combination effect of dichloroacetate (DCA) or niclosamide (Nic) Nic in MPM. Materials and methods: The effect of a combination of DCA and Nic was studied using a panel of MPM cell lines (H28, MSTO-211H, H226, H2052, and H2452). Cell viability was monitored by MTT assay. Glycolysis, oxidative phosphorylation, glucose, glycogen, pyruvate, lactate, citrate, succinate and ATP levels were determined by corresponding ELISA. Apoptosis, mitochondrial transmembrane potential, cell cycle analysis, hydrogen peroxide and superoxide were investigated by flow cytometry. Cell migration and colony formation were investigated by transwell migration and colony formation assays respectively. The in vivo effect was confirmed using 211H and H226 nude mice xenograft models. Results and conclusion: Cell viability was reduced. Disturbance of glycolysis and/or oxidative phosphorylation resulted in downregulation of glycogen, citrate and succinate. DCA and/or Nic increased apoptosis, mitochondrial transmembrane depolarization, G2/M arrest and reactive oxygen species. Moreover, DCA and/or Nic suppressed cell migration and colony formation. Furthermore, a better initial tumor suppressive effect was induced by the DCA/Nic combination compared with either drug alone in both 211H and H226 xenograft models. In H226 xenografts, DCA/Nic increased median survival of mice compared with single treatment. Single drug and/or a combination disturbed the Warburg effect and activated apoptosis, and inhibition of migration and proliferation in vivo. In conclusion, dichloroacetate and/or niclosamide showed a tumor suppressive effect in MPM in vitro and in vivo, partially mediated by disturbance of glycolysis/oxidative phosphorylation, apoptosis, ROS production, G2/M arrest, and suppression of migration and proliferation.

  Copyright © 2022 Lam, Yan, Lam, Feng, Khan, Chen, Ko and Ho.

• Editorial: Novel agents and combinations for treatment of malignant pleural mesothelioma in pre-clinical models. S.K. Lam, S.E. Mutsaers. 2022;13:1015959. Editorial PubMed · Publisher · Free full text

• How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies. B.W.S. Robinson, A.J. Redwood, J. Creaney. 2022;13:858557. Review PubMed · Publisher · Free full text

  Abstract

  Asbestos-induced preclinical mouse models of mesothelioma produce tumors that are very similar to those that develop in humans and thus represent an ideal platform to study this rare, universally fatal tumor type. Our team and a number of other research groups have established such models as a stepping stone to new treatments, including chemotherapy, immunotherapy and other approaches that have been/are being translated into clinical trials. In some cases this work has led to changes in mesothelioma treatment practice and over the last 30 years these models and studies have led to trials which have improved the response rate in mesothelioma from less than 10% to over 50%. Mouse models have had a vital role in that improvement and will continue to play a key role in the future success of mesothelioma immunotherapy. In this review we focus only on these original inbred mouse models, the large number of preclinical studies conducted using them and their contribution to current and future clinical therapy for mesothelioma.

  Copyright © 2022 Robinson, Redwood and Creaney.

• Improved Survival and Quality of Life Through an Integrative, Multidisciplinary Oncological Approach: Pathophysiological Analysis of Four Clinical Cancer Cases and Review of the Literature. M. Berretta, A. Morra, R. Taibi, et al. 2022;13:867907. PubMed · Publisher · Free full text

  Abstract

  Objectives: According to the National Cancer Institute, the integrative medicine (IM) approach to medical care combines standard medicine with complementary and alternative medicine practices that have proved safe and effective. Methods: We describe the clinical cases of four patients with malignant pleural mesothelioma (MPM), diffuse malignant peritoneal mesothelioma (DMPM), intrahepatic cholangiocarcinoma, and breast cancer (BC) who received supportive treatment (ST) according to an IM approach after the failure of standard cancer treatments or the appearance of serious adverse events caused by antiblastic chemotherapy. The critical role of complementary drugs in reducing the side effects of cancer treatments and normalizing the white cell count is especially apparent in the case of the patient with metastatic BC, who experienced prolonged neutropenia. Results: The IM approach was well-tolerated and had no adverse side effects. It improved the quality of life (QoL) of all patients and in two cases extended overall survival. Conclusion: The extended clinical and instrumental response to IM of the patients with malignant mesothelioma and the improved health-related QoL and good tolerance of the ST demonstrated in all cases support the value of this approach in patients whose cancer therapies have failed but who show a good performance status. Our data require confirmation in a well-designed prospective clinical trial.

  Copyright © 2022 Berretta, Morra, Taibi, Monari, Maurea, Ippolito, Tirelli, Fiorica, Montella, Facchini, Quagliariello and Montopoli.

• Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment. X.M. Xue, Y.Y. Liu, X.M. Chen, et al. 2022;13:1064032. PubMed · Publisher · Free full text

  Abstract

  Background: Ecto-5'-nucleotidase (NT5E) encodes the cluster of differentiation 73 (CD73), whose overexpression contributes to the formation of immunosuppressive tumor microenvironment and is related to exacerbated prognosis, increased risk of metastasis and resistance to immunotherapy of various tumors. However, the prognostic significance of NT5E in pan-cancer is obscure so far. Methods: We explored the expression level of NT5E in cancers and adjacent tissues and revealed the relationship between the NT5E expression level and clinical outcomes in pan-cancer by utilizing the UCSC Xena database. Then, correlation analyses were performed to evaluate the relationship between NT5E expression and immune infiltration level via EPIC, MCP-counter and CIBERSORT methods, and the enrichment analysis were employed to identify NT5E-interacting molecules and functional pathways. Furthermore, we conducted single-cell analysis to explore the potential role of NT5E on single-cell level based on the CancerSEA database. Meanwhile, gene set enrichment analysis (GSEA) in single-cell level was also conducted in TISCH database and single-cell signature explorer was utilized to evaluate the epithelial-mesenchymal transition (EMT) level in each cell type. Results: The expression level of NT5E was aberrant in almost all cancer types, and was correlated with worse prognosis in several cancers. Notably, NT5E overexpression was related to worse overall survival (OS) in pancreatic adenocarcinoma (PAAD), head and neck squamous cell carcinoma (HNSC), mesothelioma (MESO), stomach adenocarcinoma (STAD), uveal melanoma (UVM) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (p < 0.01). NT5E-related immune microenvironment analysis revealed that NT5E is associated positively with the degree of infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells in most cancers. Enrichment analysis of cellular component (CC) demonstrated the critical part of NT5E played in cell-substrate junction, cell-substrate adherens junction, focal adhesion and external side of plasma membrane. Finally, single-cell analysis of NT5E illuminated that EMT function of CAFs was elevated in basal cell carcinoma (BCC), skin cutaneous melanoma (SKCM), HNSC and PAAD. Conclusion: NT5E could serve as a potential prognostic biomarker for cancers. The potential mechanism may be related to the upregulated EMT function of CAFs, which provides novel inspiration for immunotherapy by targeting CAFs with high NT5E expression.

  Copyright © 2022 Xue, Liu, Chen, Tao, Liu, Zhou, Zhang, Wang, Jiang, Ding, Shen, Zhang, Yang and Wang.

• A Glimpse in the Future of Malignant Mesothelioma Treatment. G. Pezzicoli, M. Rizzo, M. Perrone, et al. 2021;12:809337. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The landscape of effective therapy for this disease remained unchanged in the last two decades. Recently, however, the introduction of Immune Checkpoint Inhibitors (ICIs) led to small, but nevertheless, promising improvements. However, many efforts are still needed to radically improve the prognosis of MMe. In this review, we analyze all those therapeutic strategies for MMe that are still in a preclinical or early clinical phase of development. In particular, we focus on novel antiangiogenic drugs and their possible combination with immunotherapy. Furthermore, we describe also more complex strategies such as microRNA-loaded vectors, oncolytic viruses, and engineered lymphocytes.

  Copyright © 2021 Pezzicoli, Rizzo, Perrone, Minei, Mutti and Porta.

• Novel Therapeutic Targets and Immune Dysfunction in Malignant Pleural Mesothelioma. M. Lapidot, S.V. Saladi, R. Salgia, et al. 2021;12:806570. Review PubMed · Publisher · Free full text

  Abstract

  Advances in the treatment of malignant pleural mesothelioma (MPM) have been disappointing, despite the apparent need for new therapeutic options for this rare and devastating cancer. Drug resistance is common and surgical intervention has brought benefits only to a subset of patients. MPM is a heterogenous disease with a surprisingly low mutation rate and recent sequencing efforts have confirmed alterations in a limited number of tumor suppressors that do not provide apparent insights into the molecular mechanisms that drive this malignancy. There is increasing evidence that epigenetic regulation leads to immune evasion and transformation in MPM. Further, the low efficacy of immune checkpoint inhibitors is consistent with a suppression of genes involved in the anti-tumor immune response. We review three promising emerging therapeutic targets (STAT3, KDM4A, heparanase) and highlight their potential effects on the immune response.

  Copyright © 2022 Lapidot, Saladi, Salgia and Sattler.

• Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations. D.B. Oien, S. Sarkar Bhattacharya, J. Chien, et al. 2021;12:750352. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a rare cancer with disproportionately higher death rates for shipping and mining populations. These patients have few treatment options, which can be partially attributed to limited chemotherapy responses for tumors. We initially hypothesized that quinacrine could be combined with cisplatin or pemetrexed to synergistically eliminate mesothelioma cells. The combination with cisplatin resulted in synergistic cell death and the combination with pemetrexed was not synergistic, although novel artificially-generated pemetrexed-resistant cells were more sensitive to quinacrine. Unexpectedly, we discovered cells with NF2 mutations were very sensitive to quinacrine. This change of quinacrine sensitivity was confirmed by NF2 ectopic expression and knockdown in NF2 mutant and wildtype cell lines, respectively. There are few common mutations in mesothelioma and inactivating NF2 mutations are present in up to 60% of these tumors. We found quinacrine alters the expression of over 3000 genes in NF2-mutated cells that were significantly different than quinacrine-induced changes in NF2 wildtype cells. Changes to NF2/hippo pathway biomarkers were validated at the mRNA and protein levels. Additionally, quinacrine induces a G1 phase cell cycle arrest in NF2-mutated cells versus the S phase arrest in NF2-wildtype cells. This study suggests quinacrine may have repurposing potential for a large subset of mesothelioma patients.

  Copyright © 2021 Oien, Sarkar Bhattacharya, Chien, Molina and Shridhar.

• Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma. Y. Sato, M. Tomita, T. Soga, et al. 2021;12:718675. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an invasive malignancy that develops in the pleural cavity, and antifolates are used as chemotherapeutics for treating. The majority of antifolates, including pemetrexed (PMX), inhibit enzymes involved in purine and pyrimidine synthesis. MPM patients frequently develop drug resistance in clinical practice, however the associated drug-resistance mechanism is not well understood. This study was aimed to elucidate the mechanism underlying resistance to PMX in MPM cell lines. We found that among the differentially expressed genes associated with drug resistance (determined by RNA sequencing), TYMS expression was higher in the established resistant cell lines than in the parental cell lines. Knocking down TYMS expression significantly reduced drug resistance in the resistant cell lines. Conversely, TYMS overexpression significantly increased drug resistance in the parental cells. Metabolomics analysis revealed that the levels of dTMP were higher in the resistant cell lines than in the parental cell lines; however, resistant cells showed no changes in dTTP levels after PMX treatment. We found that the nucleic acid-biosynthetic pathway is important for predicting the efficacy of PMX in MPM cells. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5'-UTR of TYMS may promote its expression in drug-resistant cells. Our findings indicate that the intracellular levels of dTMP are potential biomarkers for the effective treatment of patients with MPM and suggest the importance of regulatory mechanisms of TYMS expression in the disease.

  Copyright © 2021 Sato, Tomita, Soga, Ochiai and Makinoshima.

2010s

• Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma. M. Benvenuto, R. Mattera, J.I. Sticca, et al. 2018;9:1269. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies.

• Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells. Y. Sato, S. Matsuda, A. Maruyama, et al. 2018;9:1129. PubMed · Publisher · Free full text

  Abstract

  Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM.

• Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy. D.B. Oien, T. Garay, S. Eckstein, et al. 2017;8:970. PubMed · Publisher · Free full text

  Abstract

  Reactive oxygen species (ROS) can promote or inhibit tumorigenesis. In mesothelioma, asbestos exposure to serous membranes induces ROS through iron content and chronic inflammation, and ROS promote cell survival signaling in mesothelioma. Moreover, a current chemotherapy regimen for mesothelioma consisting of a platinum and antifolate agent combination also induce ROS. Mesothelioma is notoriously chemotherapy-resistant, and we propose that ROS induced by cisplatin and pemetrexed may promote cell survival signaling pathways, which ultimately may contribute to chemotherapy resistance. In The Cancer Genome Atlas datasets, we found AXL kinase expression is relatively high in mesothelioma compared to other cancer samples. We showed that ROS induce the phosphorylation of AXL, which was blocked by the selective inhibitor BGB324 in VMC40 and P31 mesothelioma cells. We also showed that cisplatin and pemetrexed induce the phosphorylation of AXL and Akt, which was also blocked by BGB324 as well as by N-acetylcysteine antioxidant. AXL knockdown in these cells enhances sensitivity to cisplatin and pemetrexed. Similarly, AXL inhibitor BGB324 also enhances sensitivity to cisplatin and pemetrexed. Finally, higher synergy was observed when cells were pretreated with BGB324 before adding chemotherapy. These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed. These results suggest AXL inhibition combined with the current chemotherapy regimen may represent an effective strategy to enhance the efficacy of chemotherapy in mesothelioma. This is the first study, to our knowledge, on chemotherapy-induced activation of AXL and cell survival pathways associated with ROS signaling.

• In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma. L. Masuelli, M. Benvenuto, R. Mattera, et al. 2017;8:373. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients' survival is poor. The polyphenol 4',5,7,-trihydroxyflavone Apigenin (API) is a "multifunctional drug". Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-κB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API.

• Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors. P. Tiberio, E. Cavadini, L. Cleris, et al. 2017;8:226. PubMed · Publisher · Free full text

  Abstract

  4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors.

• The epithelium in idiopathic pulmonary fibrosis: breaking the barrier. A. Camelo, R. Dunmore, M.A. Sleeman, et al. 2014;4:173. Review PubMed · Publisher · Free full text

  Abstract

  Idiopathic pulmonary fibrosis is a progressive disease of unknown etiology characterized by a dysregulated wound healing response that leads to fatal accumulation of fibroblasts and extracellular matrix (ECM) in the lung, which compromises tissue architecture and lung function capacity. Injury to type II alveolar epithelial cells is thought to be the key event for the initiation of the disease, and so far both genetic factors, such as mutations in telomerase and MUC5B genes as well as environmental components, like cigarette smoking, exposure to asbestos and viral infections have been implicated as potential initiating triggers. The injured epithelium then enters a state of senescence-associated secretory phenotype whereby it produces both pro-inflammatory and pro-fibrotic factors that contribute to the wound healing process in the lung. Immune cells, like macrophages and neutrophils as well as activated myofibroblasts then perpetuate this cascade of epithelial cell apoptosis and proliferation by release of pro-fibrotic transforming growth factor beta and continuous deposition of ECM stiffens the basement membrane, altogether having a deleterious impact on epithelial cell function. In this review, we describe the role of the epithelium as both a physical and immunological barrier between environment and self in the homeostatic versus diseased lung and explore the potential mechanisms of epithelial cell injury and the impact of loss of epithelial cell permeability and function on cytokine production, inflammation, and myofibroblast activation in the fibrotic lung.

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