title: All trans retinoic acid nanodisks enhance retinoic acid receptor mediated apoptosis and cell cycle arrest in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is characterized by translocation t(11;14)(q13;q32), aggressive clinical behaviour, and poor patient outcomes following conventional chemotherapy. New treatment approaches are needed that target novel biological pathways. All trans retinoic acid (ATRA) is a key retinoid that acts through nuclear receptors that function as ligand-inducible transcription factors. The present study evaluated cell killing effects of ATRA-enriched nanoscale delivery particles, termed nanodisks (ND), on MCL cell lines. Results show that ATRA-ND induced cell death more effectively than naked ATRA (dimethyl sulphoxide) or empty ND. ATRA-ND induced reactive oxygen species (ROS) generation to a greater extent than naked ATRA. The antioxidant, N-acetylcysteine, inhibited ATRA-ND induced apoptosis. Compared to naked ATRA, ATRA-ND enhanced G1 growth arrest, up-regulated p21and p27, and down regulated cyclin D1. At ATRA concentrations that induced apoptosis, expression levels of retinoic acid receptor-alpha (RARalpha) and retinoid X receptor-gamma (RXRgamma) were increased. Compared to naked ATRA, ATRA-ND significantly stimulated transcriptional activity of RARA in a model carcinoma cell line. Furthermore, the RAR antagonist, Ro 41-5253, inhibited ATRA-ND induced ROS generation and prevented ATRA-ND induced cell growth arrest and apoptosis. In summary, incorporation of ATRA into ND enhanced the biological activity of this retinoid in cell culture models of MCL.
authors.affiliation: Division of Haematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. a-singh@northwestern.edu
authors.forename: Amareshwar T K
authors.initials: AT
authors.lastname: Singh
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
authors.forename: Reilly J
authors.initials: RJ
authors.lastname: Anderson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Beckstead
authors.forename: Natesan
authors.initials: N
authors.lastname: Sankar
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Savita
authors.initials: S
authors.lastname: Bhalla
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Trudy M
authors.initials: TM
authors.lastname: Forte
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism / Q000473:pathology*; D053758:Nanoparticles; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D018797:Cell Cycle Proteins; D002839:Chromans; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C062521:RCC1 protein, human; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C084904:Ro 41-5253; D014212:Tretinoin