title: Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas.
abstract: Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFκB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment.
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: alfeuzanotto@hotmail.com.
authors.forename: Alfeu
authors.initials: A
authors.lastname: Zanotto-Filho
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors.forename: Elizandra
authors.initials: E
authors.lastname: Braganhol
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Karina
authors.initials: K
authors.lastname: Klafke
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Fabrício
authors.initials: F
authors.lastname: Figueiró
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Sílvia Resende
authors.initials: SR
authors.lastname: Terra
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Francis Jackson
authors.initials: FJ
authors.lastname: Paludo
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Maurílio
authors.initials: M
authors.lastname: Morrone
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Ivi Juliana
authors.initials: IJ
authors.lastname: Bristot
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Battastini
authors.affiliation: Hospital São Vicente de Paulo, Universidade de Passo Fundo (UPF), Passo Fundo, RS, Brazil.
authors.forename: Cassiano Mateus
authors.initials: CM
authors.lastname: Forcelini
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Alexander James Roy
authors.initials: AJR
authors.lastname: Bishop
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Daniel Pens
authors.initials: DP
authors.lastname: Gelain
authors.affiliation: Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: José Cláudio Fonseca
authors.initials: JCF
authors.lastname: Moreira
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051381:Rats; D000077204:Temozolomide
chemical_list: D003606:Dacarbazine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003474:Curcumin; D000077204:Temozolomide
keywords: Apoptosis; Autophagy; Curcumin; ERK1/2; Temozolomide