New insights into functional regulation in MS-based drug profiling

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport.

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“…This result on the terpenoid-backbone biosynthesis was also confirmed by KEGG enrichment analysis using the CoFRA R package (Figure 4) [24].…”

Section: Resultssupporting

confidence: 52%

“…Transcripts ≥1.5 up- or down-regulated and with an adjusted p value of 0.05 or less were considered to be significant. DAVID [62] and CoFRA [24] was used for functional enrichment of the significant regulated genes.…”

Section: Methodsmentioning

confidence: 99%

The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization

et al. 2018

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“…Complete functional regulation analysis tests for significant regulation of entities (genes, proteins) within a functional group together with significant enrichment in terms of the identification of a given functional annotated group [ 21 ]. The methodology combines functional regulation and enrichment analysis into a single visual summary.…”

Section: Resultsmentioning

confidence: 99%

“…The quantitative data for acellular BAL, BAL exosomes, patient match normal versus tumor tissue, and patient-matched normal versus mouse xenotransplant tissue were subjected to completed functional regulation analysis as previously described [ 21 ]. The quantitative data was matched against the functional categories in KEGG [ 52 ], gene ontology [ 53 ], HPRD [ 54 ], CORUM [ 55 ], and MSigDB [ 56 ].…”

Section: Methodsmentioning

confidence: 99%

Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?

Carvalho

Moraes

et al. 2020

Cancers

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Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years´ follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.

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“…Details of how we define functional enrichment based on the hypergeometric probability test have previously been described 39 40 . Functional enrichment was made by extracting all functional categories for which at least one of the samples showed a significant enrichment based on the hypergeometric probability test.…”

Section: Methodsmentioning

confidence: 99%

Bronchoalveolar Lavage Proteomics in Patients with Suspected Lung Cancer

Carvalho

Cuco

Lavareda

et al. 2017

Sci Rep

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Lung cancer configures as one of the deadliest types of cancer. The future implementation of early screening methods such as exhaled breath condensate analysis and low dose computed tomography (CT) as an alternative to current chest imaging based screening will lead to an increased burden on bronchoscopy units. New approaches for improvement of diagnosis in bronchoscopy units, regarding patient management, are likely to have clinical impact in the future. Diagnostic approaches to address mortality of lung cancer include improved early detection and stratification of the cancers according to its prognosis and further response to drug treatment. In this study, we performed a detailed mass spectrometry based proteome analysis of acellular bronchoalveolar lavage (BAL) fluid samples on an observational prospective cohort consisting of 90 suspected lung cancer cases which were followed during two years. The thirteen new lung cancer cases diagnosed during the follow up time period clustered, based on liquid chromatography-mass spectrometry (LC-MS) data, with lung cancer cases at the time of BAL collection. Hundred and thirty-tree potential biomarkers were identified showing significantly differential expression when comparing lung cancer versus non-lung cancer. The regulated biomarkers showed a large overlap with biomarkers detected in tissue samples.

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New insights into functional regulation in MS-based drug profiling

Cited by 16 publications

References 40 publications

The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization

The Antitumor Activity of a Lead Thioxanthone is Associated with Alterations in Cholesterol Localization

Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer?

Bronchoalveolar Lavage Proteomics in Patients with Suspected Lung Cancer

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