Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS Teaser Greater emphasis on marine natural products research could selectively cure multiple human ailments with fewer hazardous effects. Cancer control potential of marine natural product scaffolds through FOUNDATION REVIEW inhibition of tumor cell migration and invasion Reviews 1 2 Mudit Mudit BS Mudit Mudit and Khalid A. El Sayed Pharmacy, PhD, is an assistant professor in the 1 Department of Pharmaceutical, Social and Administrative Sciences, D’Youville College School of Pharmacy, Department of Pharmaceutical, Social and Buffalo, NY 14201, USA 2 Administrative Sciences at Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, the D’Youville College Monroe, LA 71201, USA School of Pharmacy. He is an active member of several professional organizations, including the The marine environment is a reliable source for the discovery of novel American Association of Colleges of Pharmacy, American Association of Pharmaceutical Scientists treatment options for numerous diseases. Past research efforts toward the (AAPS), American Chemical Society, and Rho Chi discovery of marine-derived anticancer agents have resulted in several Pharmacy Honor Society. He has given numerous research presentations both at regional and national commercially available marine-based drugs. The pharmaceutical value of meetings, and has been recognized by the AAPS for excellence in graduate education in the fields of Drug anticancer drugs from marine natural products (MNPs) ranges from Design and Discovery. He has also been a reviewer for US$563 billion to US$5.69 trillion. In this review, we highlight several many scientific manuscripts, research and educational grants, and annual professional meeting abstracts and marine-derived entities with the potential for cancer control and posters. prevention through the inhibition of crucial tumor cell motility and/or Khalid El Sayed, BS Pharmacy, MSc, PhD, is a migration steps involved in subsequent cancer metastases. This report also tenured professor, covers the major hurdles typically faced by the MNPs research scientific Department of Basic community. Pharmaceutical Sciences, School of Pharmacy, University of Louisiana- Monroe. Dr El Sayed is an active member in the Introduction American Society of Pharmacognosy, American Chemical Society and American Association for Cancer is one of the deadliest diseases worldwide and is the second most common cause of death Cancer Research. Dr El Sayed has more than 125 in the USA after cardiovascular diseases. It is defined as ‘a group of diseases characterized by the research publications, including nearly 50 papers on marine natural products and their use as scaffolds for uncontrolled growth and spread of abnormal cells’, according to Cancer Facts and Figures of 2016, a design of anticancer analogs, eight patents and five publication distributed by the American Cancer Society (www.cancer.org/acs/groups/content/@ book chapters. He is currently funded by the National Cancer Institute and has secured more than US$1.6 research/documents/document/acspc-047079.pdf). Approximately 1.7 million new cancer cases million in research funds during his Louisiana career. are expected to be diagnosed in 2016, with nearly 600 000 Americans projected to die from cancers. Within the next two decades, annual worldwide cancer cases are expected to rise from 14 million in 2012 to 22 million, according to the World Health Organization (www.who.int/ mediacentre/factsheets/fs297/en/). In the USA, the probability of developing invasive cancer during the lifetime of an individual is slightly less than 1 in 2 for men and slightly more than 1 in 3 for women (www.cancer.org). Prostate cancer is the most frequently diagnosed cancer in men, with an estimated 221 000 new cases in the USA expected during 2016. Similarly, more than 230 000 new cases of breast cancer are expected to be diagnosed in women in the USA. Both prostate and breast malignancies constitute the second-leading cause of cancer-related death (prostate: estimated more than 27 000 deaths; breast: estimated 40 000 deaths in 2016) in men and women in the USA, respectively. Corresponding author: Mudit, M. ([email protected]) 1359-6446/ß 2016 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2016.06.032 www.drugdiscoverytoday.com 1745 REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016 1 1 Natural products have proven to be an unparalleled source of mesylate (Halaven ), brentuximab vedotin (Adcetris ), and io- 1 molecular diversity for the discovery and development of new ta-carrageenan (Carragelose ) were approved in the USA by the drugs. The screening of natural sources, such as microbial and Food and Drug Administration (FDA), while trabectedin, ET-743 1 plant extracts and MNPs, has led to the discovery of numerous new (Yondelis ) was approved in the European Union (EU). Ziconotide pharmacologically active agents. Some of these agents have is labeled for the management of severe chronic pain in patients Reviews proved to be clinically useful drugs for the treatment of human with AIDS or cancer. It was first isolated from the venom of the diseases [1]. Aside from those drugs, which can be classified as fish-hunting marine snail Conus magus and collected in the ‘original natural products’, more drugs in clinical use or develop- Philippines under the name v-conotoxin MVIIA [13]. Ziconotide FOUNDATION REVIEW ment can be characterized as ‘semisynthetically derived from is an extremely effective analgesic with 1000-fold more potency natural products’, or ‘synthetic products based on natural product than morphine [10,14]. Omega-3 acid ethyl esters can be obtained models’ [2]. From January 1981 to December 2014, 73% (1142 out from fish oils and have been approved for reducing serum triglyc- of 1562) of the new chemical entities (NCEs) approved worldwide eride levels. These fish oils are formulated as 1-g soft-gelatin and captured across all disease states were ‘other than formal capsules comprising at least 900 mg of the ethyl esters of ome- synthetics’, including natural products and natural product-in- ga-3 fatty acids (approximately 465 mg eicosapentaenoic acid and spired drugs [3]. Furthermore, an exhaustive survey by Newman 375 mg docosahexaenoic acid) [10]. Studies suggest that severe and Cragg compiled a list of 246 approved anticancer drugs from hypertriglyceridemia, which is often associated with the risk of the 1940s to 2014 [3] and, of these, 207 were small-molecule types, coronary heart disease, can be treated with omega-3 acid ethyl excluding high-molecular-weight biologics and vaccines. In addi- esters [10]. Halichondrin B has been isolated from Halichondria tion, 77.3% (160 out of 207) of those small molecule-based ap- sponges and is a cytotoxic macrolide. However, eribulin mesylate proved anticancer agents were naturally inspired molecules, is an optimized, and much simpler, analog of halichondrin B. This suggesting that nature is a major contributor to anticancer drug optimized analog is approved for the treatment of metastatic discovery [3]. breast cancer, especially for patients who have previously received Terrestrial plants have longstanding historical medical uses; taxane- and anthracycline-based chemotherapy regimens [14]. however, marine organisms have recently been given considerable Brentuximab vedotin is derived from dolastatins that were isolated attention because of their extreme biodiversity [4,5]. These marine from Dolabella auricularia, a small sea mollusk. It is approved for organisms are widespread in oceans that cover more than 70% of the treatment of systemic anaplastic large cell lymphoma and the surface of the Earth [6]. The most important advantage of Hodgkin’s lymphoma. Approval of brentuximab in 2011 by the MNPs as potential lead entities is that they are more likely to show US FDA constituted the first new treatment option for Hodgkin ‘drug-likeness and biological friendliness when compared to total- lymphoma since 1977 [14]. The sulfated galactose polymer iota- ly synthetic molecules’, because they have been elaborated within carrageenan was recently approved for ITs antiviral properties. living systems and created to exert pharmacological activity for This polymer is derived from the red seaweeds Eucheuma and purposes of survival, chemical defense, and competitive advantage Chondrus and is currently sold as a nasal spray for the prophylaxis in their ecosystems [4,7]. There are many unique structural fea- and therapy of respiratory infections against human rhinoviruses tures present in a variety of molecules in almost every class of [10]. Similarly, Yondelis (trabectedin) isolated from the tunicate marine organism [8]. This can be attributed to the extreme chemi- Ecteinascidia turbinate, which is found in the Caribbean and the cal and physical conditions in the marine environment [8]. The Mediterranean Sea, was approved for patients with soft tissue advancement and popularity of MNPs research is evident; there sarcoma (STS) and ovarian cancer [15,16]. were only four published papers on MNPs by 1963 and only one The current pipeline of MNPs in clinical trials comprises 20 paper stating new compounds [9]. Today, the isolation of 24 662 compounds (Fig. 1) either in Phase I, II, or III clinical trials [10,17]. new compounds has been reported in 9220 published papers [9]. Recently, cytotoxic marine-derived compounds were chemically In terms of bioactive compounds, more