RESUMO
Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration-dependent and time-dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone-treated cells, atovaquone decreased ATP levels. As a consequence of mitochondrial respiration inhibition, reactive oxygen species levels were increased by atovaquone. The complete rescue of atovaquone's effects by an antioxidant suggests the important role of oxidative stress in the action of atovaquone in RCC. Importantly, atovaquone enhanced the in vitro and in vivo efficacy of 5-fluorouracil (5-FU) and interferon-α (IFN-α). Our preclinical findings suggest that atovaquone is a useful addition for RCC treatment. Our work also further demonstrates that RCC is more dependent on mitochondrial respiration than glycolysis.
Assuntos
Antineoplásicos/farmacologia , Atovaquona/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Neoplasias Renais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Atovaquona/antagonistas & inibidores , Atovaquona/uso terapêutico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Interferon-alfa/agonistas , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos SCID , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The effect of 16 alpha-acetoxy-26-hydroxycholest-4-ene-3,22-dione (SN-1) isolated from Solanum nudum Dunal (a Solanaceae traditionally used for treating fever in Colombia) on Plasmodium falciparum erythrocyte stages and its in vitro antiplasmodial activity when combined with the following conventional drugs was studied: chloroquine (CQ), amodiaquine (AQ), desethylamodiaquine (desethyl-AQ), quinine (QN), artemisinin (AR), atovaquone (ATV) and quinine (QN). It was found that SN-1 targeted trophozoites and had a synergistic effect when combined with CQ and QN; however, it had an antagonist effect when used with the other combinations.