title: Combinatorial treatment with anacardic acid followed by TRAIL augments induction of apoptosis in TRAIL resistant cancer cells by the regulation of p53, MAPK and NFκβ pathways.
abstract: TRAIL, an apoptosis inducing cytokine currently in phase II clinical trial, was investigated for its capability to induce apoptosis in six different human tumor cell lines out of which three cell lines showed resistance to TRAIL induced apoptosis. To investigate whether Anacardic acid (A1) an active component of Anacardium occidentale can sensitize the resistant cell lines to TRAIL induced apoptosis, we treated the resistant cells with suboptimal concentration of A1 and showed that it is a potent enhancer of TRAIL induced apoptosis which up-regulates the expression of both DR4 and DR5 receptors, which has been observed in the cellular, protein and mRNA levels. The death receptors upregulation consequent to A1 treatment was corroborated by the activation of p53 as well as phosphorylation of p38 and JNK MAP kinases and concomitant inactivation of NFκβ and ERK signaling cascades. Also, A1 modulated the expression of key apoptotic players like Bax, Bcl-2 and CAD along with the abatement of tumor angiogenesis in vivo in EAT mouse model. Thus, post A1 treatment the TRAIL resistant cells turned into TRAIL sensitive cells. Hence our results demonstrate that A1 can synergize TRAIL induced apoptosis through the upregulation of death receptors and downregulation of anti-apoptotic proteins in cancer context.
authors.affiliation: Molecular Oncology Lab, Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, Karnataka, 570 006, India.
authors.forename: M
authors.initials: M
authors.lastname: Harsha Raj
authors.affiliation: Molecular Oncology Lab, Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, Karnataka, 570 006, India.
authors.forename: B
authors.initials: B
authors.lastname: Yashaswini
authors.affiliation: Clinic IV: Pediatric Hematology and Oncology, Center of Pediatrics and Adolescent Medicine, University Medical Hospital, Mathildenstrasse 1, 79106, Freiburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Rössler
authors.affiliation: Molecular Oncology Lab, Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore, Karnataka, 570 006, India. salimathuom@gmail.com.
authors.forename: Bharathi P
authors.initials: BP
authors.lastname: Salimath
mesh_terms: D048729:Anacardic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048729:Anacardic Acids; D051017:Apoptosis Regulatory Proteins; D008081:Liposomes; D016328:NF-kappa B; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; C088115:anacardic acid; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3
keywords: Anacardic acid; Apoptosis; Death receptors; TRAIL