All trans retinoic acid nanodisks enhance retinoic acid receptor mediated apoptosis and cell cycle arrest in mantle cell lymphoma

• Published in: British journal of haematology Vol. 150; no. 2; pp. 158 - 169
• Main Authors: Singh, Amareshwar T.K., Evens, Andrew M., Anderson, Reilly J., Beckstead, Jennifer A., Sankar, Natesan, Sassano, Antonella, Bhalla, Savita, Yang, Shuo, Platanias, Leonidas C., Forte, Trudy M., Ryan, Robert O., Gordon, Leo I.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2010; Blackwell
• Subjects: all trans retinoic acid (ATRA); Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Benzoates - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - drug effects; Chromans - pharmacology; Drug Delivery Systems; Drug Evaluation, Preclinical; Guanine Nucleotide Exchange Factors - biosynthesis; Guanine Nucleotide Exchange Factors - drug effects; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Mantle-Cell - metabolism; Lymphoma, Mantle-Cell - pathology; mantle cell lymphoma; Medical sciences; nanodisks; Nanoparticles; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - drug effects; Nuclear Proteins - biosynthesis; Nuclear Proteins - drug effects; reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Retinoic Acid - antagonists & inhibitors; Receptors, Retinoic Acid - drug effects; Receptors, Retinoic Acid - metabolism; Retinoid X Receptors - drug effects; Retinoid X Receptors - metabolism; Transcription, Genetic - drug effects; Tretinoin - administration & dosage; Tretinoin - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Oxidative stress; nanodisks; Reactive oxygen species; Hematology; all trans retinoic acid (ATRA); Retinoid; B cell neoplasm; Malignant hemopathy; B-Lymphocyte; Non Hodgkin lymphoma; Cell death; Lymphoproliferative syndrome; Cell cycle; Mantle cell lymphoma; Cancer; Apoptosis; RAR retinoic acid receptor; Tretinoin
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2010.08209.x

Summary 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‐α (RARα) and retinoid X receptor‐γ (RXRγ) 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.