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Turning the gun on cancer: Utilizing lysosomal P-glycoprotein as a new strategy to overcome multi-drug resistance.
Seebacher, Nicole; Lane, Darius J R; Richardson, Des R; Jansson, Patric J.
Afiliación
  • Seebacher N; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales 2006, Australia.
  • Lane DJ; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales 2006, Australia.
  • Richardson DR; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales 2006, Australia.
  • Jansson PJ; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales 2006, Australia.
Free Radic Biol Med ; 96: 432-45, 2016 07.
Article en En | MEDLINE | ID: mdl-27154979
Oxidative stress plays a role in the development of drug resistance in cancer cells. Cancer cells must constantly and rapidly adapt to changes in the tumor microenvironment, due to alterations in the availability of nutrients, such as glucose, oxygen and key transition metals (e.g., iron and copper). This nutrient flux is typically a consequence of rapid growth, poor vascularization and necrosis. It has been demonstrated that stress factors, such as hypoxia and glucose deprivation up-regulate master transcription factors, namely hypoxia inducible factor-1α (HIF-1α), which transcriptionally regulate the multi-drug resistance (MDR), transmembrane drug efflux transporter, P-glycoprotein (Pgp). Interestingly, in addition to the established role of plasma membrane Pgp in MDR, a new paradigm of intracellular resistance has emerged that is premised on the ability of lysosomal Pgp to transport cytotoxic agents into this organelle. This mechanism is enabled by the topological inversion of Pgp via endocytosis resulting in the transporter actively pumping agents into the lysosome. In this way, classical Pgp substrates, such as doxorubicin (DOX), can be actively transported into this organelle. Within the lysosome, DOX becomes protonated upon acidification of the lysosomal lumen, causing its accumulation. This mechanism efficiently traps DOX, preventing its cytotoxic interaction with nuclear DNA. This review discusses these effects and highlights a novel mechanism by which redox-active and protonatable Pgp substrates can utilize lysosomal Pgp to gain access to this compartment, resulting in catastrophic lysosomal membrane permeabilization and cell death. Hence, a key MDR mechanism that utilizes Pgp (the "gun") to sequester protonatable drug substrates safely within lysosomes can be "turned on" MDR cancer cells to destroy them from within.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Miembro 1 de la Subfamilia B de Casetes de Unión a ATP / Estrés Oxidativo / Subunidad alfa del Factor 1 Inducible por Hipoxia / Neoplasias Límite: Humans Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Miembro 1 de la Subfamilia B de Casetes de Unión a ATP / Estrés Oxidativo / Subunidad alfa del Factor 1 Inducible por Hipoxia / Neoplasias Límite: Humans Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos