A natureza multifatorial da resistência a múltiplos fármacos anticancerígenos na prática clinica

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A natureza multifatorial da resistência a múltiplos fármacos anticancerígenos na prática clinica

Sexta, 10.01.2020

Vários especialistas da Acção COST STRATAGEM - “New diagnostic and therapeutic tools against multidrug resistant tumors”, reuniram esforços para escrever uma revisão atualizada, desafiante e focada nas características multidisciplinares e interdisciplinares dos cancros com resistência a múltiplos fármacos. É necessário identificar e entender os vários mecanismos moleculares responsáveis pela resistência clínica a múltiplos fármacos anticancerígenos, de modo a desenvolver novas estratégicas terapêuticas dirigidas que permitam ultrapassar a falência da terapêutica. Os diversos fatores envolvidos na resistência a múltiplos fármacos anticancerígenos destacam a relevância da nova medicina de precisão e dos tratamentos personalizados em tempo real, tendo em consideração as características individuais de cada doente com cancro.

 

Autores e Afiliações:

Yehuda G. Assaraf - The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200000, Israel

Anamaria Brozovic - Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000, Zagreb, Croatia

Ana Cristina Gonçalves - Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, FMUC, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; CNC. IBILI, University of Coimbra, Portugal

Dana Jurkovicova - Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia

Aija Linē - Latvian Biomedical Research and Study Centre, Riga, Latvia

Miguel Machuqueiro - BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, C8 Building, Campo Grande, 1749-016, Lisboa, Portugal; Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal

Simona Saponara - Department of Life Sciences, University of Siena, Siena, Italy

Ana Bela Sarmento-Ribeiro - Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, FMUC, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Group of Environment Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; CNC. IBILI, University of Coimbra, Portugal; Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

Cristina P.R. Xavier - i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal

M. Helena Vasconcelos - i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy of the University of Porto, Porto, Portugal

 

Abstract:

Curative cancer therapy remains a major challenge particularly in cancers displaying multidrug resistance (MDR). The MDR phenotype is characterized by cross-resistance to a wide array of anticancer drugs harboring distinct structures and mechanisms of action. The multiple factors involved in mediating MDR may include host factors, tumor factors as well as tumor-host interactions. Among the host factors are genetic variants and drug-drug interactions. The plethora of tumor factors involves decreased drug uptake primarily via impaired influx transporters, increased drug efflux predominantly due to the overexpression of MDR efflux transporters of the ATP-binding cassette superfamily or due to drug efflux mediated by extracellular vesicles (EVs) or drug-loaded lysosomes undergoing exocytosis, deregulation of cell death mechanisms (i.e. anti-apoptotic modalities), enhanced DNA damage repair, epigenetic alterations and/or deregulation of microRNAs. The intratumor heterogeneity and dynamics, along with cancer stem cell plasticity, are important tumor factors. Among the tumor-host interactions are the role of the tumor microenvironment, selective pressure of various stressor conditions and agents, acidic pH and the intracellular transfer of traits mediated by EVs. The involvement of these diverse factors in MDR, highlights the need for precision medicine and real-time personalized treatments of individual cancer patients. In this review, written by a group of researchers from COST Action STRATAGEM “New diagnostic and therapeutic tools against multidrug resistant tumors”, we aim to bring together these multi-disciplinary and interdisciplinary features of MDR cancers. Importantly, it is becoming increasingly clear that deciphering the molecular mechanisms underlying anticancer drug resistance, will pave the way towards the development of novel precision medicine treatment modalities that are able to surmount distinct and well-defined mechanisms of anticancer drug resistance.

 

 

Revista: Drug Resistance Updates

 

Link: https://www.ncbi.nlm.nih.gov/pubmed/31585396