Investigating USP42 Mutation as Underlying Cause of Familial Non-Medullary Thyroid Carcinoma.

In a family with Familial Non-Medullary Thyroid Carcinoma (FNMTC), our investigation using Whole-Exome Sequencing (WES) uncovered a novel germline USP42 mutation [p.(Gly486Arg)]. USP42 is known for regulating p53, cell cycle arrest, and apoptosis, and for being reported as overexpressed in breast and gastric cancer patients. Recently, a USP13 missense mutation was described in FNMTC, suggesting a potential involvement in thyroid cancer. Aiming to explore the USP42 mutation as an underlying cause of FNMTC, our team validated the mutation in blood and tissue samples from the family. Using immunohistochemistry, the expression of USP42, Caspase-3, and p53 was assessed. The USP42 gene was silenced in human thyroid Nthy-Ori 3-1 cells using siRNAs. Subsequently, expression, viability, and morphological assays were conducted. p53, Cyclin D1, p21, and p27 proteins were evaluated by Western blot. USP42 protein was confirmed in all family members and was found to be overexpressed in tumor samples, along with an increased expression of p53 and cleaved Caspase-3. siRNA-mediated USP42 downregulation in Nthy-Ori 3-1 cells resulted in reduced cell viability, morphological changes, and modifications in cell cycle-related proteins. Our results suggest a pivotal role of USP42 mutation in thyroid cell biology, and this finding indicates that USP42 may serve as a new putative target in FNMTC.

Using a Dual CRISPR/Cas9 Approach to Gain Insight into the Role of LRP1B in Glioblastoma.

LRP1B remains one of the most altered genes in cancer, although its relevance in cancer biology is still unclear. Recent advances in gene editing techniques, particularly CRISPR/Cas9 systems, offer new opportunities to evaluate the function of large genes, such as LRP1B. Using a dual sgRNA CRISPR/Cas9 gene editing approach, this study aimed to assess the impact of disrupting LRP1B in glioblastoma cell biology. Four sgRNAs were designed for the dual targeting of two LRP1B exons (1 and 85). The U87 glioblastoma (GB) cell line was transfected with CRISPR/Cas9 PX459 vectors. To assess LRP1B-gene-induced alterations and expression, PCR, Sanger DNA sequencing, and qRT-PCR were carried out. Three clones (clones B9, E6, and H7) were further evaluated. All clones presented altered cellular morphology, increased cellular and nuclear size, and changes in ploidy. Two clones (E6 and H7) showed a significant decrease in cell growth, both in vitro and in the in vivo CAM assay. Proteomic analysis of the clones' secretome identified differentially expressed proteins that had not been previously associated with LRP1B alterations. This study demonstrates that the dual sgRNA CRISPR/Cas9 strategy can effectively edit LRP1B in GB cells, providing new insights into the impact of LRP1B deletions in GBM biology.

Temporary prey storage along swarm columns of army ants: an adaptive strategy for successful raiding?

While pillaging the brood of other ant colonies, Eciton army ants accumulate prey in piles, or caches, along their foraging trails. Widely documented, these structures have historically been considered as by-products of heavy traffic or aborted relocations of the ants' temporary nest, or bivouac. However, we recently observed that caches of the hook-jawed army ant, Eciton hamatum, appeared independently from heavy traffic or bivouac relocations. In addition, the flow of prey through caches varied based on the quantity of prey items workers transported. As this suggested a potential adaptive function, we developed agent-based simulations to compare raids of caching and non-caching virtual army ants. We found that caches increased the amount of prey that relatively low numbers of raiders were able to retrieve. However, this advantage became less conspicuous-and generally disappeared-as the number of raiders increased. Based on these results, we hypothesize that caches maximize the amount of prey that limited amounts of raiders can retrieve, especially as prey colonies coordinately evacuate their brood. In principle, caches also allow workers to safely collect multiple prey items and efficiently transport them to the bivouac. Further field observations are needed to test this and other hypotheses emerging from our study.

BAG2 prevents Tau hyperphosphorylation and increases p62/SQSTM1 in cell models of neurodegeneration.

BACKGROUND: Protein aggregates are pathological hallmarks of many neurodegenerative diseases, however the physiopathological role of these aggregates is not fully understood. Protein quality control has a pivotal role for protein homeostasis and depends on specific chaperones. The co-chaperone BAG2 can target phosphorylated Tau for degradation by an ubiquitin-independent pathway, although its possible role in autophagy was not yet elucidated. In view of this, the aim of the present study was to investigate the association among protein aggregation, autophagy and BAG2 levels in cultured cells from hippocampus and locus coeruleus as well as in SH-SY5Y cell line upon different protein aggregation scenarios induced by rotenone, which is a flavonoid used as pesticide and triggers neurodegeneration. METHODS AND RESULTS: The present study showed that rotenone exposure at 0.3 nM for 48 h impaired autophagy prior to Tau phosphorylation at Ser199/202 in hippocampus but not in locus coeruleus cells, suggesting that distinct neuron cells respond differently to rotenone toxicity. Rotenone induced Tau phosphorylation at Ser199/202, together with a decrease in the endogenous BAG2 protein levels in SH-SY5Y and hippocampus cell culture, which indicates that rotenone and Tau hyperphosphorylation can affect this co-chaperone. Finally, it has been shown that BAG2 overexpression, increased p62/SQSTM1 levels in cells from hippocampus and locus coeruleus, stimulated LC3II recycling as well as prevented the raise of phosphorylated Tau at Ser199/202 in hippocampus. CONCLUSIONS: Results demonstrate a possible role for BAG2 in degradation pathways of specific substrates and its importance for the study of cellular aspects of neurodegenerative diseases.

Social media as a tool for surgical education: a qualitative systematic review.

BACKGROUND: Social media use has exploded, attaining a significant influence within medicine. Previous studies have denoted the use of social media in various surgical specialties as a means to exchange professional ideas and improve the conference experience and at the same time, some have assessed its feasibility as a method of education. This systematic review aims to characterize the use of social media as a tool for general surgery education. METHODS: A systematic review of several databases from each database inception was conducted following the PRISMA guidelines. The JBI's critical appraisal tools were used to assess quality of the studies. RESULTS: A total of 861 articles were identified of which 222 were duplicates removed. The titles and abstracts from the remaining 639 abstracts were screened and 589 were excluded. The remaining 51 full articles were analyzed for eligibility, of which 24 met inclusion criteria and were included in the systematic review. These studies covered the general surgery specialty, of which 11 (n = 46%) focused on the laparoscopic surgical approach, 1 (n = 4%) on robotic-assisted surgical procedures, 1 (n = 4%) on both surgical approaches previously mentioned and 11 (n = 46%) on the general surgery specialty regardless of the surgical approach or technique. CONCLUSIONS: Advantages that SM offers should be considered, and content creators and institutions should help collectively to make sure that the content being published is evidence and guideline-based so its use it is taken to the maximum benefit.

LRP1B Expression as a Putative Predictor of Response to Pegylated Liposomal Doxorubicin Treatment in Ovarian Cancer.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is among the most active therapies for recurrent/progressive ovarian cancer (OC). Low-density lipoprotein receptor-related protein 1B (LRP1B) is one of the 10 most significantly deleted genes in human cancers. It mediates endocytosis of several factors from the cellular environment including liposomes. Although the LRP1B role in cancer has not been fully disclosed, its contribution to resistance to liposomal therapies has been hypothesized. This study aimed to evaluate the impact of LRP1B protein as a possible marker of response to PLD in patients with OC. METHODS: LRP1B expression and response to PLD were analyzed in OC cell lines by qRT-PCR and PrestoBlue viability assay, respectively. LRP1B protein expression was evaluated for the first time, in tumor samples from PLD-treated patients and controls (other chemotherapies) by immunohistochemistry. Association of LRP1B staining score (determined based on intensity and percentage of positively stained cells) with clinicopathological features, response to therapy and survival outcomes was evaluated. RESULTS: OC cells with increased expression of LRP1B were more sensitive to PLD. LRP1B staining score was associated with clinicopathological features, response to therapy, and survival outcomes. Higher LRP1B levels were associated with prolonged progression-free survival. This association was more evident in patients treated with PLD and in responders to PLD. CONCLUSION: Our results support a possible role of LRP1B as a predictor of response to PLD in patients with OC.

Endoscopic onlay repair for ventral hernia and rectus abdominis diastasis repair: Why so many different names for the same procedure? A qualitative systematic review.

BACKGROUND: A subcutaneous endoscopic onlay repair for ventral hernia with an anterior plication of diastasis recti (DR) has been published under different names in different countries. The aim of this systematic review is to assess the safety and feasibility of different named techniques with the same surgical concept. METHODS: The PRISMA guidelines were followed during all stages of this systematic review. The MINORS score system was used to perform qualitative assessment of all studies included in this review. Recommendations were then summarized for the following pre-defined key items: protocol, research question, search strategy, study eligibility, data extraction, study designs, risk of bias, publication bias, heterogeneity, and statistical analysis. RESULTS: The systematic literature search found 2548 articles, 317 of which were duplicates and excluded from analysis. The titles and abstracts from the remaining 2231 articles were assessed. After careful evaluation, 2125 articles were determined to be unrelated to our study and subsequently excluded. The full text of the remaining 106 articles was thoroughly assessed. Case reports, editorials, letters to the editor, and general reviews were then excluded. A total of 13 articles were ultimately included for this review, describing a similar subcutaneous endoscopic approach for repair of concomitant ventral hernias and rectus diastasis defined under nine different named techniques on 716 patients. The number of patients in those studies varied from 10 to 201. The mean operative time varied from 68.5 to 195 min. The most common complication was seroma, followed by pain requiring intervention, hematoma, and surgical site infection. CONCLUSIONS: There are a few technique variations described in different studies, but with no significant differences in outcomes. We, therefore, propose to unify these procedures under one term, ENDoscopic Onlay Repair (ENDOR). This technique has shown to be effective and safe, with seroma being the most common complication.

Methylation profile of the ADRB3 gene and its association with lipid profile and nutritional status in adults.

BACKGROUND: Defects in DNA methylation have been shown to be associated with metabolic diseases such as obesity, dyslipidemia, and hypercholesterolemia. To analyze the methylation profile of the ADRB3 gene and correlate it with lipid profile, lipid intake, and oxidative stress based on malondialdehyde (MDA) and total antioxidant capacity (TAC), homocysteine and folic acid levels, nutritional status, lifestyle, and socioeconomic variables in an adult population. A cross-sectional epidemiological study representative of the East and West regions of the municipality of João Pessoa, Paraíba state, Brazil, enrolled 265 adults of both genders. Demographic, lifestyle, and socioeconomic questionnaires and a 24-h recall questionnaire were applied by trained interviewers' home. Nutritional and biochemical evaluation (DNA methylation, lipid profile, MDA, TAC, homocysteine and folic acid levels) was performed. RESULTS: DNA hypermethylation of the ADRB3 gene, analyzed in leukocytes, was present in 50% of subjects and was associated with a higher risk of being overweight (OR 3.28; p = 0.008) or obese (OR 3.06; p = 0.017), a higher waist-hip ratio in males (OR 1.17; p = 0.000), greater intake of trans fats (OR 1.94; p = 0.032), higher LDL (OR 2.64; p = 0.003) and triglycerides (OR 1.81; p = 0.031), and higher folic acid levels (OR 1.85; p = 0.022). CONCLUSIONS: These results suggest that epigenetic changes in the ADRB3 gene locus may explain the development of obesity and non-communicable diseases associated with trans-fat intake, altered lipid profile, and elevated folic acid. Because of its persistence, DNA methylation may have an impact in adults, in association with the development of non-communicable diseases. This study is the first population-based study of the ADRB3 gene, and the data further support evaluation of ADRB3 DNA methylation as an effective biomarker.

Decrease of the DNA methylation levels of the ADRB3 gene in leukocytes is related with serum folate in eutrophic adults.

BACKGROUND: DNA methylation has been evidenced as a potential epigenetic mechanism related to various candidate genes to development of obesity. Therefore, the objective of this study was to evaluate the DNA methylation levels of the ADRB3 gene by body mass index (BMI) in a representative adult population, besides characterizing this population as to the lipid profile, oxidative stress and food intake. METHODS: This was a cross-sectional population-based study, involving 262 adults aged 20-59 years, of both genders, representative of the East and West regions of the municipality of João Pessoa, Paraíba state, Brazil, in that were evaluated lifestyle variables and performed nutritional, biochemical evaluation and DNA methylation levels of the ADRB3 gene using high resolution melting method. The relationship between the study variables was performed using analyses of variance and multiple regression models. All results were obtained using the software R, 3.3.2. RESULTS: From the stratification of categories BMI, was observed a difference in the average variables values of age, waist-to-height ratio, waist-to-hip ratio, waist circumference, triglycerides and intake of trans fat, which occurred more frequently between the categories "eutrophic" and "obesity". From the multiple regression analysis in the group of eutrophic adults, it was observed a negative relationship between methylation levels of the ADRB3 gene with serum levels of folic acid. However, no significant relation was observed among lipid profile, oxidative stress and food intake in individuals distributed in the three categories of BMI. CONCLUSIONS: A negative relationship was demonstrated between methylation levels of the ADRB3 gene in eutrophic adults individuals with serum levels of folic acid, as well as with the independent gender of BMI, however, was not observed relation with lipid profile, oxidative stress and variables of food intake. Regarding the absence of relationship with methylation levels of the ADRB3 gene in the categories of overweight, mild and moderate obesity, the answer probably lies in the insufficient amount of body fat to initiate inflammatory processes and oxidative stress with a direct impact on methylation levels, what is differently is found most of the times in exacerbated levels in severe obesity.

Influence of the C677T Polymorphism of the MTHFR Gene on Oxidative Stress in Women With Overweight or Obesity: Response to a Dietary Folate Intervention.

The C677T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR) is related to folate metabolism and can alter the levels of biochemical markers.Objective: Investigate the influence of the MTHFR C677T polymorphism on the effects of a dietary folate intervention on oxidative stress in women with overweight or obesity.Methods: Forty-eight adult women with overweight or obesity were subjected to a 24-hour dietary recall, anthropometric measurements, biochemical analysis, and genotyping of the MTHFR C677T polymorphism. They were allocated by convenience sampling to 2 groups, which received 300 g of folate-rich vegetables containing 191 µg/d (Group 1) (n = 24) or 95 µg/d (Group 2) (n = 24) of folate for 8 weeks.Results: The dietary intervention increased the serum folic acid levels in the 2 analyzed groups. The intervention with 191 µg/d of folate led to relevant results in terms of homocysteine levels (p = 0.0005) and total antioxidant capacity (p = 0.0261); the effect was larger among carriers of the TT genotype.Conclusions: The study demonstrated the beneficial effect of folate intake in terms of a TAC elevation for the CC and TT genotypes of the MTHFR C677T polymorphism, an increase in folic acid levels for all genotypes, and a reduction in the Hcy levels for the TT genotype in response to an intervention consisting of an intake of 191 µg/d of folate supplied by vegetables.

OPNa Overexpression Is Associated with Matrix Calcification in Thyroid Cancer Cell Lines.

Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells.

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

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.

Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors.

BACKGROUND: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. METHODS: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. RESULTS: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. CONCLUSIONS: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.

Multidrug resistant tumour cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells.

BACKGROUND: Multidrug resistance (MDR) is a serious impediment to cancer treatment, with overexpression of drug efflux pumps such as P-glycoprotein (P-gp) playing a significant role. In spite of being a major clinical challenge, to date there is no simple, minimally invasive and clinically validated method for diagnosis of the MDR phenotype using non-tumour biological samples. Recently, P-gp has been found in extracellular vesicles (EVs) shed by MDR cancer cells. This study aimed to compare the EVs shed by MDR cells and their drug-sensitive cellular counterparts, in order to identify biomarkers of MDR. METHODS: Two pairs of MDR and drug-sensitive counterpart tumour cell lines were studied as models. EVs were characterized in terms of size and molecular markers and their protein content was investigated by proteomic analysis and Western blot. RESULTS: We found that MDR cells produced more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart. EVs from MDR cells contained P-gp and presented a different content of proteins known to be involved in the biogenesis of EVs, particularly in the biogenesis of exosomes. CONCLUSIONS: The determination of the size and of this particular protein content of EVs shed by tumour cells may allow the development of a minimally-invasive simple method of detecting and predicting MDR. GENERAL SIGNIFICANCE: This work describes for the first time that cancer multidrug resistant cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells, carrying a specific content of proteins involved in EV biogenesis that could be further studied as biomarkers of MDR.

A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells.

Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.

An Aqueous Extract of Tuberaria lignosa Inhibits Cell Growth, Alters the Cell Cycle Profile, and Induces Apoptosis of NCI-H460 Tumor Cells.

Tuberaria lignosa (Sweet) Samp. is found in European regions, and has antioxidant properties due to its composition in ascorbic acid and phenolic compounds. Given its traditional use and antioxidant properties, the tumor cell growth inhibitory potential of aqueous extracts from T. lignosa (prepared by infusion and decoction) was investigated in three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and HCT-15 (human colorectal adenocarcinoma). Both extracts inhibited the growth of these cell lines; the most potent one being the T. lignosa extract obtained by infusion in the NCI-H460 cells (GI50 of approximately 50 µg/mL). Further assays were carried out with this extract in NCI-H460 cells. At 100 µg/mL or 150 µg/mL it caused an increase in the percentage of cells in the G0/G1 phase and a decrease of cells in S phase of the cell cycle. Additionally, these concentrations caused an increase in the percentage of apoptotic cells. In agreement, a decrease in total poly (ADP-ribose) polymerase (PARP) and pro-caspase 3 levels was found. In conclusion, the T. lignosa extract obtained by infusion was more potent in NCI-H460 cells, altering the cell cycle progression and inducing apoptosis. This work highlights the importance of T. lignosa as a source of bioactive compounds with tumor cell growth inhibitory potential.

Modulation of Autophagy by a Thioxanthone Decreases the Viability of Melanoma Cells.

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N10-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI50 concentration (3.6 µM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity.

Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.