RESUMEN
Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.
Asunto(s)
Antineoplásicos , Proliferación Celular , Complejo I de Transporte de Electrón , Mitocondrias , Proteínas de Saccharomyces cerevisiae , Animales , Humanos , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Antineoplásicos/farmacología , Ratones , Línea Celular Tumoral , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desacopladores/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Ratas , NADH Deshidrogenasa/metabolismo , NADH Deshidrogenasa/antagonistas & inhibidoresRESUMEN
Extracellular vesicles (EVs), derived from the cell, display a phospholipid bilayer membrane that protects the cargo molecules from degradation and contributes to increasing their stability in the bloodstream and tumor targeting. EVs are interesting in regard to the delivery of photosensitizers (PSs) used in the photodynamic therapy (PDT), as they allow us to overcome the limitations observed with liposomes. In fact, liposomal formulation of meta-tetra(hydroxyphenyl)chlorin (mTHPC) (Foslip®), one of the most potent clinically approved PSs, is rapidly destroyed in circulation, thus decreasing in vivo PDT efficacy. mTHPC-EV uptake was evaluated in vitro in a 3D human colon HT-29 microtumor and in vivo study was performed in HT-29 xenografted mice. The obtained data were compared with Foslip®. After intravenous injection of the mTHPC formulations, biodistribution, pharmacokinetics and PDT-induced tumor regrowth were evaluated. In a 3D model of cells, mTHPC-EV uptake featured a deeper penetration after 24h incubation compared to liposomal mTHPC. In vivo results showed a considerable improvement of 33% tumor cure with PDT treatment applied 24h after injection, while 0% was observed after Foslip®/PDT. Moreover, 47 days were required to obtain ten times the initial tumor volume after mTHPC-EVs/PDT compared to 30 days for liposomal mTHPC. In conclusion, compared to Foslip®, mTHPC-EVs improved mTHPC biodistribution and PDT efficacy in vivo. We deduced that a major determinant factor for the improved in vivo PDT efficacy is the deep mTHPC intratumor penetration.