N-óxidos de isoquinolinaquinona com mecanismos de ação divergentes induzem sensibilidade colateral contra células cancerígenas resistentes a múltiplos fármacos

Trabalho recentemente publicado na revista “European Journal of Pharmacology" pela Doutora Mélanie Barbosa, Doutor Ryan D. Kruschel et al., demonstrou o potencial de dois N-óxidos de isoquinolinaquinona (RK2 e RK3) como promissores candidatos para as próximas fases de desenvolvimento de fármacos contra cancros resistentes a múltiplos fármacos, especificamente relacionados com a sobreexpressão de ABCB1. Este trabalho é o resultado de uma colaboração da Prof. Helena Vasconcelos do i3S, Universidade do Porto – Portugal, com o Prof. Florence McCarthy, da Escola de Química da Universidade de Cork, Irlanda.

Autores e Afiliações:

Mélanie A.G. Barbosa* - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, 4200-135, Porto, Portugal; FFUP – Faculty of Pharmacy of the University of Porto, 4050-313, Porto, Portugal

Ryan D. Kruschel* - School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, T12 K8AF, Ireland

Maria João Almeida - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, 4200-135, Porto, Portugal

Rúben F. Pereira - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Biofabrication Group, INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge de Viterbo Ferreira, 228, 4050-313, Porto, Portugal

Cristina P.R. Xavier - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, 4200-135, Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, 4585-116, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, Gandra, 4585-116, Portugal

Florence O. McCarthy - School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, T12 K8AF, Ireland

M. Helena Vasconcelos - i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, 4200-135, Porto, Portugal; FFUP – Faculty of Pharmacy of the University of Porto, 4050-313, Porto, Portugal

* These authors contributed equality to this work.

Abstract:

Multidrug resistance (MDR) is a major challenge in cancer research. Collateral sensitizers, compounds that exploit the enhanced defense mechanisms of MDR cells as weaknesses, are a proposed strategy to overcome MDR. Our previous work reported the synthesis of two novel Isoquinolinequinone (IQQ) N-oxides that induce collateral sensitivity in MDR ABCB1-overexpressing non-small cell lung cancer (NSCLC) and colorectal cancer cells. Herein, we aimed to investigate underlying mechanisms of antitumor and collateral sensitivity activity of these compounds. We evaluated their effect on cancer cell viability, proliferation, cell cycle profile, and studied their cytotoxicity in non-tumorigenic cells. Their antitumor effect was further studied using NSCLC and colorectal cancer MDR spheroids. To understand underlying collateral sensitivity mechanisms, we assessed the effect on rhodamine-123 accumulation, ROS production, GSH/GSSG balance and expression of key proteins associated with metabolism and redox balance. Both compounds reduced the viability of MDR cells, as 2D cultures or as spheroids, without decreasing the growth of a human nontumorigenic cell line, and increased rhodamine-123 accumulation in MDR NCI-H460/R cells. Moreover, RK2 increased ROS, disrupted GSH balance, and altered expression of proteins associated with oxidative stress protection, particularly in NCI-H460/R cells. The collateral sensitivity effect of RK3 could not be attributed to redox balance disruption, but increased IDH1 expression following treatment suggests a potential metabolic shift in MDR cells. These findings highlight RK2 and RK3 as promising candidates for next stages of drug development. Their distinct mechanisms of action could lead to therapeutic solutions for MDR-related cancers, specifically linked to ABCB1 overexpression.

Revista: European Journal of Pharmacology

Link:  https://pubmed.ncbi.nlm.nih.gov/39725135/