Inibição do transporte de monocarboxilatos potencia a citotoxicidade do 5-Fluorouracilo

As células cancerígenas dependem maioritariamente da glicólise para obtenção de energia, produzindo grandes quantidades de lactato que é exportado para o microambiente tumoral por transportadores de monocarboxilatos (MCTs). Neste estudo explorámos estes transportadores como novos alvos terapêuticos, por si só ou combinados com 5- Fluorouracilo (5-FU), um medicamento anticancerígeno usado no tratamento do carcinoma colorectal (CRC).

Observamos que a inibição da atividade e expressão dos MCTs diminui a viabilidade celular, interrompeu o metabolismo glicolítico, inibiu a proliferação e levou à morte celular. De salientar que a ação do 5-FU foi potenciada quando combinado com a inibição do transporte de lactato.

Estes resultados demonstram o papel importante dos MCTs na manutenção e sobrevivência do CRC, assim como sugerem o uso destes transportadores como novos alvos terapêuticos em combinação com terapias convencionais usadas no tratamento do CRC.

Autores e afiliações:

Ricardo Amorim^a,b, Céline Pinheiro^a,b,c,d, Vera Miranda-Gonçalves^a,b, Helena Pereira^e,

Mary P. Moyer^f, Ana Preto^e, Fátima Baltazar^a,b

^a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

^b ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

^c Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

^d Barretos School of Health Sciences Dr. Paulo Prata – FACISB, Barretos, Sao Paulo, Brazil

^e Centre of Molecular and Environmental Biology (CBMA)/Department of Biology, University of Minho, Braga, Portugal

^f INCELL Corporation, San Antonio, TX, USA

Abstract:

Cancer cells rely mostly on glycolysis to meet their energetic demands, producing large amounts of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). The role of MCTs in the survival of colorectal cancer (CRC) cells is scarce and poorly understood. In this study, we aimed to better understand this issue and exploit these transporters as novel therapeutic targets alone or in combination with the CRC classical chemotherapeutic drug 5-Fluorouracil.

For that purpose, we characterized the effects of MCT activity inhibition in normal and CRC derived cell lines and assessed the effect of MCT inhibition in combination with 5-FU.

Here, we demonstrated that MCT inhibition using CHC (α-cyano-4-hydroxycinnamic acid), DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid) and quercetin decreased cell viability, disrupted the glycolytic phenotype, inhibited proliferation and enhanced cell death in CRC cells. These results were confirmed by specific inhibition of MCT1/4 by RNA interference. Notably, we showed that 5-FU cytotoxicity was potentiated by lactate transport inhibition in CRC cells, either by activity inhibition or expression silencing.

These findings provide novel evidence for the pivotal role of MCTs in CRC maintenance and survival, as well as for the use of these transporters as potential new therapeutic targets in combination with CRC conventional therapy.

Revista: Cancer Letters

Link: http://www.cancerletters.info/article/S0304-3835(15)00355-9/abstract?cc=y=