Please cite this article in press as: S.M. Patel, et al., Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases, Semin Cancer Biol (2016), http://dx.doi.org/10.1016/j.semcancer.2016.03.002 ARTICLE IN PRESS G Model YSCBI-1243; No. of Pages 16 Seminars in Cancer Biology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer Review Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases Shradha M. Patel a , Kalyan C. Nagulapalli Venkata b , Piyali Bhattacharyya c , Gautam Sethi d,e , Anupam Bishayee b,∗ a College of Biomedical Sciences, Larkin Health Sciences Institute, Miami, FL 33169, USA b Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL 33169, USA c School of Health Sciences, University of Turabo, Gurabo, PR 00778, USA d Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore e School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia article info Article history: Received 27 November 2015 Received in revised form 19 March 2016 Accepted 21 March 2016 Available online xxx Keywords: Cancer Chemopreventive effect Therapeutic effect Phytoconstituents abstract Throughout time, plants have often displayed medicinal properties that have been underscored. We often derive medicines involved in treating cancer from components in plants. Azadirachta indica, com- monly known as “neem”, has been used to treat different ailments in many Asian countries. Due to its widespread beneficial uses, A. indica has often been referred to as “the wonder tree” or “nature’s drug store”. Various parts of this plant, including, leaves, flowers, fruits, seeds, roots, bark and oil, produce a large number of phytochemicals with various biological and pharmacological activities. The numerous biological activities of the phytoconstituents of A. indica explain its beneficial uses for the prevention and therapy of cancer. The chemopreventive and anticancer therapeutic efficacy of A. indica fractions and compounds could be explained by multiple cellular and molecular mechanisms, including free radical scavenging, carcinogen-detoxification, DNA repair, cell cycle alteration, programmed cell death (apoptosis) and autophagy, immune surveillance, anti-inflammatory, anti-angiogenic, anti-invasive and anti-metastatic activities as well as their ability to modulate several dysregulated oncogenic signaling pathways. This article aims to present the collective and critical analysis of multiple phytoconstituents of A. indica and their molecular mechanisms implicated in cancer chemopreventive and therapeutic effects based on published preclinical and clinical results. Current limitations and future directions of research on this medicinal plant are also critically discussed. © 2016 Elsevier Ltd. All rights reserved. 1. Introduction Azadirachta indica (family: Meliaceae), known as neem, nimtree and Indian Lilac, was first discovered in India about 4500 years ago. Neem has been given the Latinized name A. indica, which is derived from the Persian language and literally means “the free tree of India” [1]. Various parts of neem tree, including leaves, flow- ers, fruits, seeds and bark, find extensive use in traditional systems of medicine (e.g., Ayurveda, Unani and Siddha) for treating various human diseases, including tumor [2–4]. Due to its tremendous ther- ∗ Corresponding author at: Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA. E-mail addresses: abishayee@ULarkin.org, abishayee@gmail.com (A. Bishayee). URL: http://mailto:abishayee@ULarkin.org (A. Bishayee). apeutic potential, neem is also referred to as “Village pharmacy”, “Tree of the 21st century” and “A tree for solving global problems” [1,5]. Today, neem tree can be found in at least 30 countries in Asia, Africa, Australia as well as Central and South Americas [1]. A. indica can grow in dry and hot climates, allowing it to tolerate a tem- perature of 50–98 ◦ F [2]. A. indica has a low tolerance for rainfall allowing it to grow best in poor soils that are sandy, deep and have a pH of about 6.2–7 [2]. Usually, A. indica tree is found in dry, tropi- cal or subtropical locations; however, it can also be found along the sandy riverbanks in Australia [2]. The tree (Fig. 1A) is known to grow to approximately 15–20 m high and can live for about 200 years [1]. Since the tree develops a deep and strong tap root, the tree branches spread out widely and form an oval crown [2]. The oil from A. indica is usually from the seed and branches of the tree. The bark is brown and vertically http://dx.doi.org/10.1016/j.semcancer.2016.03.002 1044-579X/© 2016 Elsevier Ltd. All rights reserved.