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QIAGEN Cancer Drug Targets Array file containing the raw data (Ct information) for the qPCR of all the conditions (both A549 and SW900 cell lines).

Supplementary Figures: Figure S1. Set of tambjamine analogues investigated; Figure S2. General reaction scheme; Figure S3. 1H NMR (DMSO-d6) of compound 3.HCl; Figure S4. 13C (DMSO-d6) of compound 3.HCl; Figure S5. HRMS (EI) of compound 3; Figure S6. 1H NMR (DMSO-d6) of compound 4.HCl; Figure S7. 13C (DMSO-d6) of compound 4.HCl; Figure S8. 13C dept (DMSO-d6) of compound 4.HCl; Figure S9. HRMS (EI) of compound 4.; Figure S10. 1H NMR (CDCl3) of compound 5.HCl; Figure S11. 13C NMR (CDCl3) of compound 5.HCl; Figure S12. 13C dept NMR (CDCl3) of compound 5.HCl; Figure S13. HRMS (EI) of compound 5.; Figure S14. 1H NMR (CDCl3) of compound 6.HCl; Figure S15. 13C NMR (CDCl3) of compound 6.HCl; Figure S16. HRMS (EI) of compound 6.; Figure S17. 1H NMR (CDCl3) of compound 7.HCl; Figure S18. 13C NMR (CDCl3) of compound 7.HCl; Figure S19. 13C dept NMR (CDCl3) of compound 7.HCl; Figure S20. HRMS (EI) of compound 7.; Figure S21. 1H NMR (CDCl3) of compound 8.HCl; Figure S22. 13C NMR (CDCl3) of compound 8.HCl; Figure S23. 13C dept NMR (CDCl3) of compound 8.HCl; Figure S24. HRMS (EI) of compound 8.; Figure S25. 1H NMR (CDCl3) of compound 9.HCl; Figure S26. 13C NMR (CDCl3) of compound 9.HCl; Figure S27. 13C dept NMR (CDCl3) of compound 9.HCl; Figure S28. HRMS (EI) of compound 9.; Figure S29. 1H NMR (CDCl3) of compound 10.HCl; Figure S30. 13C NMR (CDCl3) of compound 10.HCl; Figure S31. 13C dept NMR (CDCl3) of compound 10.HCl; Figure S32. HRMS (EI) of compound 10; Figure S33. 1H NMR (CDCl3) of compound 11.HOAc; Figure S34. 13C NMR (CDCl3) of compound 11.HOAc; Figure S35. 13C dept NMR (CDCl3) of compound 11.HOAc; Figure S36. HRMS (EI) of compound 11; Figure S37. Dose response curves in A549, DMS53, SW900 and H460 cells; Figure S38. Dose response curves in human lung tumor-derived primay cultures; Figure S39. Array validation using TaqMan gene expression assays; Figure S40. Cell cycle assay by flow cytometry; Figure S41. Western blot of apoptotic markers in the DMS53 cell line; Figure S42. Body weight recording; Supplementary Tables: Table S1. Applied biosystem probes list used for the TaqMan gene expression assays; Table S2. List of altered genes in the cancer drug targets QIAGEN RT2 Profiler Array for the SW900 cell line; Supplementary Materials and Methods: Synthesis and characterization; Cell viability; TaqMan assays; Gene expression; Cell cycle; Western blot; Mice weight.

Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. This apoptotic inhibitor has a relevant role in both the promotion of cancer cell survival and in the inhibition of cell death. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer. Currently, there are several survivin inhibitors under clinical evaluation, although more specific and efficient survivin inhibitors are being developed. Moreover, novel combination regimens targeting survivin together with other therapeutic approaches are currently being designed and assessed. In this review, recent progress in the therapeutic options targeting survivin for cancer treatment is analyzed. Direct survivin inhibitors and their current development status are explored. Besides, the major signaling pathways implicated in survivin regulation are described and different therapeutic approaches involving survivin indirect inhibition are evaluated. Finally, promising novel inhibitors under preclinical or clinical evaluation as well as challenges of developing survivin inhibitors as a new therapy for cancer treatment are discussed., Consejería de Educación, Junta de Castilla y León. Grant Number: BU092U16 Instituto de Salud Carlos III. Grant Number: FIS PI18/00441

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic.

Para poder evaluar la percepción que tienen los caficultores frente a la certificación Rainforest Alliance (RA), en el año 2014, se aplicaron 58 encuestas personalizadas a caficultores certificados con el RA de las provincias comuneras y guanenta, departamento de Santander. Este trabajo se enfocó en varios tipos de investigación: “Descriptiva, explicativa, y exploratoria” porque no solo se basó en los factores externos e internos, también fue importante explorar las relaciones socioeconómicas, ambientales y poder describir la percepción de los productores sobre la certificación y la realidad de como la experimentan los caficultores certificados con el sello RA. Los resultados indican que varios requisitos establecidos por la Norma de Agricultura Sostenible (NAS) de RA, ya se cumplían por parte de los caficultores antes de estar certificados, como ofrecer en las fincas buenas condiciones de pago y trato justo a los trabajadores, efectuar prácticas de conservación de suelos, llevar registros contables y de labores en la finca. En este estudio se encontró que la gran mayoría de caficultores certificados en este municipio son pequeños y medianos productores los cuales tienen áreas entre 0 a 20 hectáreas cultivadas en su gran mayoría en café variedad Castillo y variedad Colombia. Muchos de estos caficultores encuestados tienen poco tiempo de haber obtenido el sello RA entre 0 a 5 Años y el que más tiempo lleva con el sello son 12 años. Algunos de ellos cuentan con 2 o más sellos entre los cuales se destaca los sellos Nespresso, Orgánico, 4C, y Practice. Desde la percepción que tienen los caficultores del municipio del valle de san José y con base en los resultados de la investigación podemos decir que muchos no tenían ningún conocimiento de la norma Rainforest Alliance y mucho menos de los beneficios que obtendrían de esta. Algunos si admitieron que venían presentando una necesidad y que a través de la implementación de la norma Rainforest Alliance querían suplir. Los caficultores encuestados manifestaron que el hecho de poder contar con nuevos canales de comercialización, y bonificaciones en el precio del café en el mercado por carga, fueron los motivos para que empezaran a implementar Rainforest Alliance en sus fincas. Otro tema que podemos concluir es que muchos de ellos consideraron un motivo fundamental para certificarse la gestión de la federación Nacional de cafeteros por incluirlos en un grupo selecto y la facilidad de financiamiento y acompañamiento para la implementación del sello. También se puede concluir en esta investigación fue la necesidad que tenían los caficultores de tener una agricultura amigable con el medio ambiente y ser sostenibles con el tiempo, ya que hoy en día se debe proteger el medio ambiente que nos queda y tratar de recuperar el que hemos deteriorado.Adicionalmente esta investigación nos permite concluir que el factor económico también incidió a la hora de tomar decisiones; ya que ellos veían que otros caficultores del gremio recibían mayores ingresos y que adicionalmente les crearon una gran expectativa económica por involucrarse en este proceso. Otro punto importante para concluir fue la claridad del proceso ya que como caficultores eran conscientes en que adquirir Rainforest Alliance les generaría una gran responsabilidad, gran trabajo y un gasto económico en todos y cada uno de los aspectos sobre los que trata la norma en sus 10 principios y que debían darle continuidad al proceso.

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer., Spanish Government and EU funds through the Fondo de Investigaciones Sanitarias (FIS, project PI13/ 00089) and from La Marat o de TV3 Foundation (project 20132730) to R. P erez-Tom as. R. Ramos was supported by the Sociedad Espa~nola de Neumología y Cirugía Tor acica (SEPAR, Project 017/2013), R. Quesada by the Consejería de Educación de la Junta de Castilla y León (project BU340U13) and by the La Marat o de TV3 Foundation (project 20132732) and A. Villanueva by the FIS (project PI13/01339).

Lung cancer is the leading cause of cancer-related deaths worldwide, hence novel treatments for this malignancy are eagerly needed. Since natural-based compounds represent a rich source of novel chemical entities in drug discovery, we have focused our attention on tambjamines, natural compounds isolated from marine invertebrates that have shown diverse pharmacological activities. Based on these structures, we have recently identified the novel indole-based tambjamine analog 21 (T21) as a promising antitumor agent, which modulates the expression of apoptotic proteins such as survivin. This antiapoptotic protein plays an important role in carcinogenesis and chemoresistance. In this work, we have elucidated the molecular mechanism by which the anticancer compound T21 exerts survivin inhibition and have validated this protein as a therapeutic target in different lung cancer models. T21 was able to reduce survivin protein levels in vitro by repressing its gene expression through the blockade of Janus kinase/Signal Transducer and Activator of Transcription-3 (JAK/STAT3)/survivin signaling pathway. Interestingly, this occurred even when the pathway was overstimulated with its ligand interleukin 6 (IL-6), which is frequently overexpressed in lung cancer patients who show poor clinical outcomes. Altogether, these results show T21 as a potent anticancer compound that effectively decreases survivin levels through STAT3 inhibition in lung cancer, appearing as a promising therapeutic drug for cancer treatment.

Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de-ubiquitinase OTUB1 as a negative regulator of RAS mono- and di-ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild-type RAS cells. An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development. ispartof: EMBO Molecular Medicine vol:8 issue:3 pages:288-303 ispartof: location:England status: published