José Antonio Jara1, Diego Rojas2, Vicente Castro-Castillo3, Sebastián Fuentes-Retamal2, Cristian Sandoval-Acuña2, Eduardo Parra4, Mario Pavani2, Juan Diego Maya2, Jorge Ferreira5, Mabel Catalán6. 1. Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago, Chile. 2. Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile. 3. Department of Physical Chemistry and Chemistry, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile. 4. School of Medicine, Faculty of Health Sciences, University of Tarapacá, Av. General Velásquez 1775, Arica 1000007, Chile. 5. Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address: jferreir@med.uchile.cl. 6. Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address: mabelcatalan@med.uchile.cl.
Abstract
INTRODUCTION: Colorectal cancer (CRC) is a critical health issue worldwide. The high rate of liver and lung metastasis associated with CRC creates a significant barrier to effective and efficient therapy. Tumour cells, including CRC cells, have metabolic alterations, such as high levels of glycolytic activity, increased cell proliferation and invasiveness, and chemo- and radio-resistance. However, the abnormally elevated mitochondrial transmembrane potential of these cells also provides an opportunity to develop drugs that selectively target the mitochondrial functions of tumour cells. METHODS: In this work, we used a new batch of benzoic acid esters with cytotoxic activities attached to the triphenylphosphonium group as a vehicle to target tumour mitochondria and improve their activity. We evaluated the cytotoxicity, selectivity, and mechanism of action of these derivatives, including the effects on energy stress-induced apoptosis and metabolic behaviour in the human CRC cell lines HCT-15 and COLO-205. RESULTS: The benzoic acid derivatives selectively targeted the tumour cells with high potency and efficacy. The derivatives induced the uncoupling of the oxidative phosphorylation system, decreased the transmembrane potential, and reduced ATP levels while increasing AMPK activation, thereby triggering tumour cell apoptosis in both tumour cell lines tested. CONCLUSION: The benzoic acid derivatives studied here are promising candidates for assessing in vivo models of CRC, despite the diverse metabolic characteristics of these tumour cells.
INTRODUCTION:Colorectal cancer (CRC) is a critical health issue worldwide. The high rate of liver and lung metastasis associated with CRC creates a significant barrier to effective and efficient therapy. Tumour cells, including CRC cells, have metabolic alterations, such as high levels of glycolytic activity, increased cell proliferation and invasiveness, and chemo- and radio-resistance. However, the abnormally elevated mitochondrial transmembrane potential of these cells also provides an opportunity to develop drugs that selectively target the mitochondrial functions of tumour cells. METHODS: In this work, we used a new batch of benzoic acid esters with cytotoxic activities attached to the triphenylphosphonium group as a vehicle to target tumour mitochondria and improve their activity. We evaluated the cytotoxicity, selectivity, and mechanism of action of these derivatives, including the effects on energy stress-induced apoptosis and metabolic behaviour in the humanCRC cell lines HCT-15 and COLO-205. RESULTS: The benzoic acid derivatives selectively targeted the tumour cells with high potency and efficacy. The derivatives induced the uncoupling of the oxidative phosphorylation system, decreased the transmembrane potential, and reduced ATP levels while increasing AMPK activation, thereby triggering tumour cell apoptosis in both tumour cell lines tested. CONCLUSION: The benzoic acid derivatives studied here are promising candidates for assessing in vivo models of CRC, despite the diverse metabolic characteristics of these tumour cells.
Authors: Mabel Catalán; Vicente Castro-Castillo; Javier Gajardo-de la Fuente; Jocelyn Aguilera; Jorge Ferreira; Ricardo Ramires-Fernandez; Ivonne Olmedo; Alfredo Molina-Berríos; Charlotte Palominos; Marcelo Valencia; Marta Domínguez; José A Souto; José A Jara Journal: RSC Med Chem Date: 2020-08-19