Enhancing 5-FU activity in colorectal carcinoma-derived cell lines: combination with monocarboxylate transporter inhibitors and encapsulation into zeolites

Abstract

Colorectal carcinoma (CRC) is the second most common type of cancer worldwide, being mainly a disease of industrialized countries. 5-fluorouracil (5-FU) is one of the most efficient chemotherapeutic agents in the treatment of CRC although resistance to 5-FU treatment has been reported. CRC cells rely on glycolysis to obtain energy thus producing large amounts of lactate that must be released to the extracellular microenvironment by lactate transporters, namely monocarboxylate transporters (MCTs). Zeolites are crystalline aluminosilicates solids with very regular microporous structures and they have been recently considered for medical use due to their biological properties and stability in biological environments. One of the many potentially medicinal applications of zeolites is the encapsulation of different drug molecules into them so as to obtain subsequent drug delivery systems (DDSs). This work aimed at enhancing the activity of 5-FU by the combined use of MCT inhibitors and encapsulation into zeolites and exploring these methodologies as new therapeutic approaches in CRC. For that purpose, we used two CRC-derived cell lines, HCT-15 and RKO, and assessed the effects of combining MCT inhibitors (α-Cyano-4-hydroxycinnamic acid (CHC), 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS) and Quercetin) with 5-FU on cell biomass (assessed by Sulforhodamine B assay). Likewise, 5-FU was incorporated in three different zeolite structures (NaY, LTL and NanoY) and the effects on cell biomass were measured. Our results showed that the combination of MCT inhibitors with 5-FU resulted in an increase of 5-FU cytotoxic effect in both cell lines. We were also able to observe that, while no overall toxic effect was observed upon incubation of zeolites alone in both cell lines, the incorporation of 5-FU into the zeolites resulted, in general, in an increase of the cytotoxicity as well as a higher inhibitory effect on the biomass of both cell lines, as compared to 5-FU alone. Our findings provide important evidence for the exploitation of MCT inhibitors in the pharmacological therapy of CRC since we showed a benefit of combining these drugs with the conventional anticancer agent 5-FU. Moreover, this preliminary study provides evidence that zeolites constitute good systems for drug delivery in in vitro models of CRC, which can be useful in future cancer therapies.