RESUMEN
Compared to normal cells, cancer cells have a higher level of reactive oxygen species (ROS) due to aberrant metabolism and disruption of redox homeostasis which drive their proliferation and promote progression and metastasis of cancers. The altered redox balance and biological difference between normal cells and cancer cells provide a basis for the development of anticancer agents which are able to generate pharmacological ROS insults to kill cancer cells preferentially. In this study, we report a new hybrid anticancer drug, termed OSamp, which undergoes esterase- and acid-catalyzed hydrolysis to deplete antioxidant glutathione (GSH) and generate ROS, simultaneously. OSamp significantly elevated oxidative stress in cancer cells, leading to enhanced apoptotic cancer cell death through mitochondrial membrane disruption, cytochrome c release, activation of pro-caspase 3, and deactivation of STAT3 (signal transducer and activator of transcription-3). OSamp, administered intravenously, significantly suppressed the tumor growth in a mouse model of tumor xenografts without notable side effects. Oxidative stress amplifying OSamp holds tremendous potential as a new anticancer therapeutic and provides a new therapeutic paradigm which can be extended to development of hybrid anticancer drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Profármacos/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Diseño de Fármacos , Humanos , Ratones , Profármacos/química , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Peripheral artery disease (PAD) is a common circulatory disorder in which narrowed arteries limit blood flow to the lower extremity and affect millions of people worldwide. Therapeutic angiogenesis has emerged as a promising strategy to treat PAD patients because surgical intervention has been showing limited success. Leg muscles of PAD patients have significantly high level of ROS (reactive oxygen species) and the increased production of ROS is a key mechanism of initiation and progression of PAD. We have recently developed H2O2-responsive polymer PVAX, which is designed to rapidly scavenge H2O2 and release vanillyl alcohol with antioxidant and anti-inflammatory activity. In this study, we investigated the therapeutic efficacy of PVAX nanoparticles for PAD using a cell culture model and a mouse model of hindlimb ischemia. PVAX nanoparticles significantly enhanced the expression of angiogenic inducers such as vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (PECAM)-1 in human umbilical vein endothelial cells (HUVEC). PVAX nanoparticles promoted revascularization and restoration of blood perfusion into ischemic tissues by upregulating angiogenic VEGF and PECAM-1. This work demonstrates that H2O2-responsive PVAX nanoparticles facilitate therapeutic angiogenesis and hold tremendous translational potential as therapeutic systems for ischemic diseases such as PAD.
Asunto(s)
Antioxidantes/administración & dosificación , Peróxido de Hidrógeno/administración & dosificación , Nanopartículas/administración & dosificación , Enfermedad Arterial Periférica/tratamiento farmacológico , Polímeros/administración & dosificación , Animales , Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Nanopartículas/metabolismo , Enfermedad Arterial Periférica/metabolismo , Enfermedad Arterial Periférica/patología , Polímeros/metabolismoRESUMEN
Cancer cells, compared to normal cells, are under oxidative stress associated with an elevated level of reactive oxygen species (ROS) and are more vulnerable to oxidative stress induced by ROS generating agents. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells preferentially, without significant toxicity to normal cells, and great efforts have been dedicated to the development of strategies to induce cytotoxic oxidative stress for cancer treatment. Fenton reaction is an important biological reaction in which irons convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals that escalate ROS stress. Here, we report Fenton reaction-performing polymer (PolyCAFe) micelles as a new class of ROS-manipulating anticancer therapeutic agents. Amphiphilic PolyCAFe incorporates H2O2-generating benzoyloxycinnamaldehyde and iron-containing compounds in its backbone and self-assembles to form micelles that serve as Nano-Fenton reactors to generate cytotoxic hydroxyl radicals, killing cancer cells preferentially. When intravenously injected, PolyCAFe micelles could accumulate in tumors preferentially to remarkably suppress tumor growth, without toxicity to normal tissues. This study demonstrates the tremendous translatable potential of Nano-Fenton reactors as a new class of anticancer drugs.
Asunto(s)
Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Hierro/química , Hierro/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Fragmentación del ADN/efectos de los fármacos , Compuestos Ferrosos/química , Células HEK293 , Humanos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/uso terapéutico , Concentración de Iones de Hidrógeno , Radical Hidroxilo/química , Radical Hidroxilo/farmacología , Hierro/uso terapéutico , Metalocenos , Ratones , Ratones Desnudos , Micelas , Células 3T3 NIH , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Polímeros/síntesis química , Polímeros/química , Especies Reactivas de Oxígeno/metabolismo , Trasplante HeterólogoRESUMEN
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are also susceptible to further ROS insults. Cancer cells adapt to oxidative stress by upregulating antioxidant systems such as glutathione to counteract the damaging effects of ROS. Therefore, the elevation of oxidative stress preferentially in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. Here we report a dual stimuli-responsive hybrid anticancer drug QCA, which can be activated by H2O2 and acidic pH to release glutathione-scavenging quinone methide and ROS-generating cinnamaldehyde, respectively, in cancer cells. Quinone methide and cinnamaldehyde act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. We therefore anticipate that QCA has promising potential as an anticancer therapeutic agent.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Boro/farmacología , Ésteres/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Línea Celular , Cromatografía Liquida/métodos , Fragmentación del ADN , Ésteres/síntesis química , Ésteres/química , Peróxido de Hidrógeno , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Distribución Aleatoria , Especies Reactivas de Oxígeno , Espectrometría de Masas en TándemRESUMEN
Cancer cells are under oxidative stress due to a large production of reactive oxygen species (ROS), which involve in cell proliferation and cancer promotion and progression. On the other hand, ROS promotes cell death, depending on the rate of ROS production and the activity of antioxidant systems. Recently, "oxidation therapy" has arisen as a promising anticancer strategy, which can be achieved by inducing the generation of cytotoxic level of ROS or inhibiting the antioxidant systems in tumor cells. Here, we report oxidative stress amplifying nanoplatforms as novel anticancer therapeutics, which are able not only to suppress antioxidant but also to generate ROS simultaneously in acidic tumor microenvironments. The oxidative stress amplifying nanoplatforms are composed of dual pH-sensitive PBCAE copolymer, polymeric prodrug of BCA (benzoyloxycinnamaldehyde) and heme oxygenase-1 (HO-1) inhibiting zinc protoporphyrin (ZnPP). PBCAE was designed to incorporate ROS-generating BCA in its backbone via acid-cleavable acetal linkages and self-assemble to form micelles that encapsulate ZnPP. In vitro proof-of-concept studies revealed that ZnPP encapsulated in PBCAE micelles suppressed HO-1 to make cancer cells more vulnerable to BCA-induced ROS, leading to enhanced apoptotic cell death. In addition, ZnPP-loaded PBCAE micelles significantly suppressed the tumor growth in human cancer xenograft mouse models. We believe that oxidative stress amplifying micellar nanoparticles have a great potential as novel redox anticancer therapeutics.