Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer.

Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy.

BACKGROUND: Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance imaging (MRI) for imaging cell death induced by either a cytotoxic drug (irinotecan), or the apoptosis-inducing agent birinapant, in human tumour xenografts in vivo. METHODS: Nude mice bearing human SW620 colon carcinoma xenografts were treated with vehicle, irinotecan (50 mg kg(-1)) or birinapant (30 mg kg(-1)) for up to 5 days. DW-MRI was performed prior to and on days 1, 3 and 5 during treatment. Assessment of tumour apoptosis and necrosis ex vivo was used to validate the imaging findings. RESULTS: Both irinotecan and birinapant induced significant tumour growth delay. Irinotecan induced a small increase in the tumour apparent diffusion coefficient (ADC) after 1 day, with a 20 and 30% increase at days 3 and 5 respectively. ADC was unchanged in the vehicle- and birinapant-treated tumours despite a growth delay in the latter. Histological analysis showed that irinotecan increased necrosis at days 3 and 5, and induced apoptosis after 1 day, compared with vehicle. Birinapant induced apoptosis after day 3, but had no effect on tumour necrosis. CONCLUSIONS: Tumour ADC changes after irinotecan treatment were associated with the induction of a mixture of necrotic and apoptotic cell death, whereas induction of apoptosis alone with birinapant was not sufficient to induce changes in tissue microstructure that were detectable with DW-MRI. ADC is a useful non-invasive biomarker for early detection of response to cytotoxic drugs, but false negatives may arise while detecting apoptotic response to birinapant.

Estudo Etnobotânico de plantas medicinais utilizadas pela Comunidade do Sisal no município de Catu, Bahia, Brasil / Ethnobotanical study of medicinal plants used by the Sisal Community in the city of Catu, Bahia, Brazil

A utilização de plantas medicinais é instintiva nos animais, visto que alguns destes buscam raízes, cascas, folhas ou frutos na tentativa de resolver seus males. O homem, por sua vez, aprendeu a utilizar estas informações empiricamente para fazer uso destes vegetais. A medicina popular é uma importante alternativa, provavelmente, a mais usada para a cura de doenças por parte de populações indígenas, quilombolas ou rurais. A Etnobotânica, por sua vez, encarrega-se de estudar e interpretar essa relação dos homens com o mundo vegetal. Devido ao seu grande potencial biológico e cultural, o Brasil apresenta uma infinidade de conhecimentos tradicionais e espécies vegetais importantes, o que torna esse país uma grande fonte de pesquisa na área. Visando avaliar o conhecimento tradicional da população rural do Sisal, Catu/Bahia, relacionado ao uso de plantas medicinais, este trabalho iniciou-se em julho de 2009, constando de entrevistas semi-estruturadas e estruturadas, gravações, registros fotográficos, coleta do material botânico indicado nas entrevistas com os informantes, tratamento do material coletado e incorporação ao Herbário da Universidade do Estado da Bahia (HUNEB). Foram identificadas e coletadas 54 espécies distribuídas em 46 gêneros e 28 famílias, sendo Lamiacaeae e Asteraceae as mais representativas. A maioria das plantas é constituída de ervas e cultivada nos quintais dos moradores. O estudo revelou que a comunidade apresenta uma medicina popular bastante rica, com grande diversidade de espécies vegetais e usos por parte da população.

The use of medicinal plants is instinctive in animals, since some of these seek roots, bark, leaves or fruits in an attempt to cure their diseases. Man, in turn, learned to use this information on the use of these plants empirically. Folk medicine is an important alternative, probably the most used to cure diseases by indigenous peoples, Afro-descendants and rural populations. Ethnobotany, in turn, undertakes to study and interpret the relationship of men with the plant world. Because of its great biological and cultural potential, Brazil has a wealth of traditional knowledge and important plant species, what makes this country a great source of research in the area. To evaluate the traditional knowledge of the rural population of Sisal, city of Catu, state of Bahia, Brazil, related to use of medicinal plants, this work began in July 2009, consisting of semi-structured and structured interviews, recordings, photographs, collection of botanical material indicated in the interviews with informants, treatment of the collected material and incorporation into the Herbarium of the University of Bahia (HUNEB). We identified and collected 54 species in 46 genera and 28 families, being Asteraceae and Lamiacaeae the most representative. Most plants are herbs grown in the backyards of the residents. The study revealed that the community has a very rich folk medicine, with a great diversity of plant species and uses by the population.