RESUMO
BACKGROUND: Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its mechanism of action. METHODS: Multiple approaches were employed, including cell viability, cell cycle analysis, multiple measurements of apoptosis, and mitochondrial function. In addition we measured cellular metal contents and employed EPR to record redox cycling of TPEN-metal complexes. Mouse xenografts were also performed to test the efficacy of TPEN in vivo. RESULTS: We show that metal chelation using TPEN (5µM) selectively induces cell death in HCT116 colon cancer cells without affecting the viability of non-cancerous colon or intestinal cells. Cell death was associated with increased levels of reactive oxygen species (ROS) and was inhibited by antioxidants and by prior chelation of copper. Interestingly, HCT116 cells accumulate copper to 7-folds higher levels than normal colon cells, and the TPEN-copper complex engages in redox cycling to generate hydroxyl radicals. Consistently, TPEN exhibits robust anti-tumor activity in vivo in colon cancer mouse xenografts. CONCLUSION: Our data show that TPEN induces cell death by chelating copper to produce TPEN-copper complexes that engage in redox cycling to selectively eliminate colon cancer cells.
Assuntos
Quelantes/farmacologia , Neoplasias do Colo/tratamento farmacológico , Cobre/metabolismo , Etilenodiaminas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose , Linhagem Celular Tumoral , Quelantes/metabolismo , Neoplasias do Colo/patologia , Etilenodiaminas/metabolismo , Feminino , Células HCT116 , Células HT29 , Humanos , Camundongos , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Oxirredução/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ's chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ's adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.
