Efecto de la inhibición de la clusterina sobre la sensibilidad a los inhibidores de proteínas quinasas en células tumorales de mama

En la actualidad, el cáncer supone la segunda causa de muerte en el mundo, siendo el cáncer de mama la neoplasia maligna sólida más frecuentemente diagnosticada en las mujeres occidentales y la que presenta una mayor prevalencia mundial a 5 años. Después del cáncer de pulmón, el cáncer de mama supone la primera causa de muerte en mujeres de entre 40 y 55 años. Así pues, el cáncer de mama supone un problema sanitario de gran magnitud tratándose generalmente mediante la combinación de cirugía, quimioterapia y hormonoterapia. Las proteínas quinasas son reguladores clave de todos los aspectos relacionados con la aparición y desarrollo de los tumores, al controlar procesos tales como la angiogénesis, la migración celular y la apoptosis. Además, diversos estudios han revelado que pueden llegar a disminuir el umbral en el cual las células entran en apoptosis, lo que aumenta su sensibilidad frente a otros agentes antiapoptóticos. La eficacia de los inhibidores de proteínas quinasas en el tratamiento del cáncer ha sido demostrada por diversos ensayos clínicos, aunque sólo ha mostrado un efecto modesto cuando se aplica como terapia única. La proteína clusterina es una glicoproteína multifuncional altamente conservada en distintas especies y de la que se han descrito tres isoformas, la clusterina nuclear (CLUn), la clusterina citosólica (CLUc) y la clusterina secretora (CLUs). La función de ésta proteína depende en gran medida del tipo de isoforma de la que se trate, de célula en el que se expresa y del tipo concreto del mediador de la señal celular, jugando un papel muy importante en el control de la apoptosis celular. Así, mientras la CLUn tiene un papel proapoptótico, la CLUs tiene una función citoprotectora ya que inhibe la apoptosis. En este estudio se estudia el efecto que la inhibición de la expresión de la clusterina secretora, mediante el uso de oligonucleótidos antisentido u ODN y siRNA, tiene sobre la sensibilidad de las dos líneas tumorales de mama, MCF-7 y MDA-MB-231, frente a los inhibidores de proteínas quinasas H-89, Chelerythrine y Genisteina. Tras la finalización de los ensayos se comprobó que los tres inhibidores usados en el estudio aumentaron la expresión de la clusterina, como una respuesta adaptativa que mejora la supervivencia de la célula tumoral frente a un medio hostil, y que los tratamientos que incluyeron la inhibición de esta proteína mediante el uso de ODN o siRNA redujeron el número de células viables de forma más efectiva que cuando el tratamiento se realizó únicamente con los agentes citotóxicos. Finalmente, se concluye que el tratamiento combinado de inhibidores de proteínas quinasas junto con inhibidores de clusterina puede suponer una estrategia novedosa y prometedora en casos de resistencia de las células tumorales de mama a las terapias convencionales

Calcium Homeostasis in the Development of Resistant Breast Tumors.

Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.Partial funding for open access charge: Universidad de Málaga

Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance

Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistanceThe researcher Marilina García-Aranda is the benefactor of a postdoctoral contract financed by the European Social Fund—Operational Program of Andalusia 2014–2020 for the “Incorporation of Research Personnel with a PhD degree in the field of Health Sciences and Technologies in R&D and Innovation Centers of the Public Health System of Andalusia” (RH-0055-2020). This work was partially supported by grant from the University of Malaga—Consejería de Transformación Económica, Industria, Conocimiento y Universidades—Junta de Andalucia (UMA20-FEDERJA-161). Partial funding for open access charge: Universidad de Málag

Anticlusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity

Introduction: Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy. Methods: MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these. Results: Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival. Conclusion: These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses

Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance

Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistance

Targeting Receptor Kinases in Colorectal Cancer

Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment

Immunotherapy: A Challenge of Breast Cancer Treatment

Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the significant benefit of the use of conventional chemotherapy and monoclonal antibodies in the prognosis of breast cancer patients and although the recent approval of the anti-PD-L1 antibody atezolizumab in combination with chemotherapy has been a milestone for the treatment of patients with metastatic triple-negative breast cancer, immunologic treatment of breast tumors remains a great challenge. In this review, we summarize current breast cancer classification and standard of care, the main obstacles that hinder the success of immunotherapies in breast cancer patients, as well as different approaches that could be useful to enhance the response of breast tumors to immunotherapies

Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy

The interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as a great promise for cancer treatment, increasing total survival compared to standard therapy in different tumors. Despite the hopefulness of these results, a significant percentage of patients do not respond to such therapy or will end up evolving toward a progressive disease. Besides their role in PD-L1 expression, altered protein kinases in tumor cells can limit the effectiveness of PD-1/PD-L1 blocking therapies at different levels. In this review, we describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments

Protein Kinase Targets in Breast Cancer

With 1.67 million new cases and 522,000 deaths in the year 2012, breast cancer is the most common type of diagnosed malignancy and the second leading cause of cancer death in women around the world. Despite the success of screening programs and the development of adjuvant therapies, a significant percentage of breast cancer patients will suffer a metastatic disease that, to this day, remains incurable and justifies the research of new therapies to improve their life expectancy. Among the new therapies that have been developed in recent years, the emergence of targeted therapies has been a milestone in the fight against cancer. Over the past decade, many studies have shown a causal role of protein kinase dysregulations or mutations in different human diseases, including cancer. Along these lines, cancer research has demonstrated a key role of many protein kinases during human tumorigenesis and cancer progression, turning these molecules into valid candidates for new targeted therapies. The subsequent discovery and introduction in 2001 of the kinase inhibitor imatinib, as a targeted treatment for chronic myelogenous leukemia, revolutionized cancer genetic pathways research, and lead to the development of multiple small-molecule kinase inhibitors against various malignancies, including breast cancer. In this review, we analyze studies published to date about novel small-molecule kinase inhibitors and evaluate if they would be useful to develop new treatment strategies for breast cancer patients

Biomarker Identification through Proteomics in Colorectal Cancer

Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer