Table of Contents
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FOREWORD
PREFACE
Introduction
Abstract
Introduction
Approved Drugs Sourced from Marine Biota
Cancer as a Major Public Health Problem
Pathophysiology of Cancer
Anticancer Potential of Marine Organisms
Most Promising Marine Biota-Derived Anticancer Compounds for the Different Types of Human Cancer
Human Colon Cancer
Human Cervical Cancer
Blood Cancer
Mammary Cancer
Hepatic Cancer
Human Skin Cancer
Biogeography of Marine Invertebrate Species Yielding Anticancer Compounds
Major Constraints in the Development of Anticancer Drugs
CONCLUSION
REFERENCE
Marine Bio-Chemical Diversity: Promising Anticancer Groups
Abstract
INTRODUCTION
Promising Anticancer Marine Biodiversity
Marine Microalgae
Macroalgae (Seaweeds)
Mangrove Plants
Marine Invertebrates
Marine Sponges
Marine Cnidarians
Marine Bryozoans
Molluscs
Echinoderms
Tunicates
Promising Anticancer Marine Biota-derived Chemical Diversity
Predicted Total Number of Secondary Metabolites in Marine Plants and Invertebrates
Anticancer Marine Chemical Classes
Polyphenols
Polysaccharides
Alkaloids
Peptides
Antibiotics
Anticancer Chemical Diversity of Marine Biota
CONCLUSION
REFERENCE
Marine Biota-based Anticancer Drug Candidates in Pipeline
Abstract
INTRODUCTION
Approved and Marketed Anticancer Drugs Derived from Marine Sponges
Eribulin Mesylate (E7389, Halaven®)
Panobinostat (LBH-589, Farydak®)
Approved and Marketed Anticancer Drugs Derived from Marine Mollusks/Cyanobacteria Association
Brentuximab Vedotin ((SGN-35, Adcetris®)
Polatuzumab Vedotin
Enfortumab Vedotin-Eifv (Padcev®)
Disitamab Vedotin
Tisotumab Vedotin-tftv (Tivdak®)
Belantamab Mafodotin-blmf (Blenrep®)
Approved and Marketed Anticancer Drugs Derived from Marine Tunicates
Plitidepsin (Aplidin®)
Trabectedin (Yondelis®)
Lurbinectedin
Marine Biota- derived Anticancer Compounds in Clinical Trials
Anticancer Marine Species in Clinical Trials
Patented New Chemical Entities (NCEs) with Anticancer Activities from Marine Biota
Limiting Factors in the Development and Approval of Drugs from Marine Biota
Significant Challenges in the Development and Approval of Marine Drugs
CONCLUSION
REFERENCE
Anticancer Potential of Marine Bryozoans
Abstract
INTRODUCTION
Anticancer and Cytotoxic Metabolites of Marine Bryozoans
Anticancer Alkaloid Compounds of Marine Bryozoans
Amathia convoluta
Amathia tortuosa
Amathia wilsoni
Aspidostoma giganteum
Biflustra perfragilis
Caulibugula intermis
Chartella papyracea
Cryptosula pallasiana
Flustra foliacea
Paracribricellina cribraria
Pterocella vesiculosa
Securiflustra securifrons
Tegella spitzbergensis
Terminoflustra (Chartella) membranaceotruncata
Virididentula (Bugula) dentata
Anticancer Lactone Compounds of Marine Bryozoans
Bugula neritina
Bryostatin-1
Bryostatin-5
Bryostatin-8
Bryostatin-19
Bryostatin Analogues
Myriapora truncata
Cryptosula pallasiana
CONCLUSION
REFERENCE
Medicinal Chemistry and Marine Life
(Volume 1)
Anticancer Drugs Sourced from Marine Life
Authored by
Ramasamy Santhanam
Fisheries College and Research Institute
Tamil Nadu Veterinary and Animal Sciences University Thoothukudi-628008
India
Santhanam Ramesh
Karuna College of Pharmacy
Kerala University of Health Sciences
Thirumittacode, Palakkad 679 533, Kerala
India
Subbiah Balasundari
Dr.M.G.R. Fisheries College and Research Institute
Tamil Nadu Fisheries University, Thalainayeru
Tamil Nadu-614712
India
&
Sheba R. David
School of Pharmacy, University of Wyoming, Laramie Wyoming 82071-3375
USA
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FOREWORD
I am very much pleased to write my Foreword for this inter-disciplinary title "Medicinal Chemistry and Marine Life: Anticancer Drugs Sourced from Marine Life" relating to an untouched aspect of Fisheries and Pharmaceutical disciplines.
Cancer is an increasing public health hazard and about 60% of the anticancer drugs of natural origin are presently in use to treat this disease. Owing to the tumor cells resistance to drugs, and undesirable side effects observed with the synthetic drugs, there is an urgent need for the development of new anticancer drugs. In this regard, the marine environment, an exceptional reservoir of anticancer compounds, has paved way for further investigations on the utilization of its vast biodiversity. Comparing with terrestrial organisms, marine organisms do not have a distinguished history of use in traditional medicine. But during the last 50 years, advances in new technologies and engineering opened up the marine environment to large scale scientific exploration. Despite considerable challenges, 11 marine biota-derived anticancer drugs arrived in the market and are currently used in therapeutics.
The present title, first of its kind deals with the major constituents of marine life with promising anticancer compounds and in my opinion, this publication could serve as a potential resource for teachers and students of both Marine and Pharmaceutical Sciences besides serving as a reference for anticancer agents from marine source.
I congratulate the authors for their timely contribution.
K.N. Selvakumar
Tamil Nadu Veterinary and Animal Sciences University
Chennai, India
PREFACE
Cancer remains one of the most life-threatening diseases and its prevalence is increasing worldwide especially in countries that are witnessing urbanization and rapid industrialization changes. In 2018 alone, about 18 million new cases of cancer were reported globally, resulting in approximately 10 million deaths. Cancer treatments do not have potent medicine as the currently available drugs are causing side effects in some instances. Hence, identifying novel effective drugs is urgently needed, and many ongoing research programs are in the process of identifying new anti-cancer drugs from marine organisms which are considered “blue drug banks” of unique anti-cancer compounds with diverse groups of chemical structures. Seven marine-based pharmaceuticals have so far been approved for marketing; 23 compounds are in clinical trials between phases I and III; and over one thousand compounds isolated from marine organisms are undergoing preclinical studies. It is worthy of mention here that among those marine organism-derived compounds in clinical use, four compounds viz. cytarabine (Cytosar®), trabectedin (Yondelis®), eribulin mesylate (Halaven®) and the conjugated antibody brentuximab vedotin (Acentris®) are used in the treatment of cancer.
Though a few books are presently available on marine natural products and pharmaceutical marine life, a comprehensive volume dealing with the biodiversity of marine organisms yielding anticancer compounds has not so far been published. This interdisciplinary publication first of its kind would answer this long-felt need. It deals mainly with the ecology, and biology of marine organisms yielding anticancer compounds and their mechanism of action. It is hoped that the present publication when brought out would be of great use as a standard text-cum-reference for teachers, students, and researchers of various disciplines such as biomedical sciences, pharmaceutical sciences, marine biology, and fisheries science; a valuable reference for libraries of colleges and universities; and as a guide for the pharmaceutical industries involved in the development of new marine-derived anticancer drugs.
Ramasamy Santhanam
Fisheries College and Research Institute
Tamil Nadu Veterinary and Animal Sciences University, Thoothukudi-628008
IndiaSanthanam Ramesh
Karuna College of Pharmacy, Kerala University of Health Sciences
Thirumittacode, Palakkad 679 533, Kerala
IndiaSubbiah Balasundari
Dr.M.G.R. Fisheries College and Research Institute, Tamil Nadu Fisheries University Thalainayeru, Tamil Nadu 614712
India
&Sheba R. David
Introduction
Ramasamy Santhanam,Subbiah Balasundari,Sheba R. David
Abstract
This chapter deals with the approved drugs sourced from marine biota, the pathophysiology of cancer, the anticancer potential of marine organisms, the most promising marine biota-derived anticancer compounds for the different types of human and cancer, biogeography of marine invertebrate species yielding anti cancer com-pounds, major constraints in the development of anticancer drugs and the remedial measures.
Keywords: Approved marine drugs, Anticancer marine compounds, Cancer pathophysiology, Constraints in marine anticancer drug development, Human cancer types, Marine biota, Remedial measures.
Introduction
The total global biodiversity in terms of both prokaryotic and eukaryotic organisms has been estimated as 500 × 106 species and in the marine ecosystems, about 250,000 species have been described. These marine organisms produce secondary metabolites as their defense tools to resist predators and facilitate their survival in extreme environmental conditions such as variations in temperatures, salinity, pressure, etc. Such secondary metabolites of marine organisms have been reported to offer extraordinary chemical and pharmacological scope. While marine flora such as seaweeds and mangroves have been used for medicinal purposes worldwide since ancient times, marine invertebrate animals have attracted the attention of researchers only in the last 50 years. It is worthy of mention here that less than 5% of the deep sea has only been explored till now and less than 0.01% of the deep-sea floor has been sampled thoroughly [1].
Approved Drugs Sourced from Marine Biota
The marine environment has been reported to possess immeasurable chemical diversity and it is an extraordinary resource for therapeutically important chemicals. The unique structural scaffolds and biological modes of action of these
chemicals make them lead compounds in drug discovery. Research on the secondary metabolites of marine organisms began only in the 1950s with Bergmann and coworkers’ discovery of spongothymidine and spongouridine derived from the Caribbean sponge Tectitethya crypta. The reports on the geographic origin of the marine compounds showed that Australia contributed almost a quarter (24%) of these compounds followed by the South China Sea (18%) and the Pacific Ocean (17%) [2].To date, more than 28,000 compounds derived from marine organisms have been reported and more than 1000 new marine-derived compounds have been discovered each year since 2008. Although the number of promising bioactive compounds from the marine biota is on the increase, the search for marine biota-derived drugs is relatively recent, and only in the middle part of the 20th century, the scientists began to systematically probe the seas and oceans for new drugs. Today, the pipeline process from the basic research of a bioactive molecule to the regulatory approval by the Food and Drug Administration (FDA) takes about 15 years and costs several million dollars. However, it is also worth of mentioning here that less than 12% of the potential drugs get final approval [3]. The stages and time estimates in the development and approval of a drug are given in Table 1.
Table 1Stages and Time Estimates in the Development and Approval of Drugs [3].StageEstimated Time (Yrs)Basic Research and Drug discovery5Preclinical Trials1.5Clinical Trials (Phase I,II & III)*6FDA Review2Large Scale Manufacturing2
* Number of Volunteers: Phase I, Tens; Phase II, Hundreds; Phase III, Thousands.
Cancer as a Major Public Health Problem
Cancer has been reported to be a major public health problem worldwide and is the second leading cause of death in the United States. As per the report of the US National Cancer Institute, 21 million new cases may appear in the coming two decades. Africa, Asia, and Central and South America are considered to be the most vulnerable countries where 7 out of 10 deaths are due to malignant neoplasms termed as cancer. However, tumor and cancer are also interchangeably used occasionally. The deadliest cancers are believed to be lung cancer, breast cancer, prostate cancer, colon cancer, pancreatic cancer, liver cancer, ovarian cancer, leukemia, non-Hodgkin's lymphoma, and corpus and uterus cancer. Among the usual cancer treatment forms viz. surgery, radiotherapy, and chemotherapy, the former two are primarily indicated for solid tumors and chemotherapy assumes greater significance as this systemic drug-based treatment is known to interfere with the process of growth and cell division in tumor cells. Further, this chemotherapy is currently undergoing a significant revolution due to the introduction of a very large number of new arsenal drugs and less side effects of such target-oriented drugs. However, these drugs have not yielded the desired results; and recurrence of tumor and onset of metastasis often occur with such therapies. Therefore, there is an urgent need to search for new compounds with greater therapeutic potency and fewer side effects. In this connection, the seas and oceans could play an important role with their huge pharmaceutical biodiversity in general and anticancer potential in particular.
Pathophysiology of Cancer
In the development of cancer in the human body, several stages are involved. A normal cell may get damaged by either endogenous genetic and biological factors or exogenous factors like human diet and body mutation. Such damaged cells may either attain apoptosis (cell death) or undergo uncontrolled cell division which leads to mass forming and finally neoplasia. The neoplasia is nothing but the uncontrolled, abnormal growth of cells which is termed a neoplasm or tumor. The tumor may be benign (gentle) or become malignant (cancer). Generally, a balance between proliferation and programmed cell death is maintained in the form of apoptosis under normal conditions by regulating both processes tightly. On the other hand, in carcinogenesis, normal cells are transformed into cancer cells.
Anticancer Potential of Marine Organisms
Owing to their diverse and highly complex habitats and lifestyle, the marine species represent a largely unexplored source of potential anticancer agents. The anticancer compounds are mainly derived from mollusk/cyanobacterium (blue-green algae) (64%), sponge (14%), tunicate(14%), bacterium (4%) and fungus (4%) in that order. It is also worthy of mention here that 7 marine biota-based drugs have so far been approved for marketing; 23 compounds are in clinical trials between phases I and III; and more than one thousand compounds are undergoing preclinical studies. Further, among those marine biota-derived drugs in clinical use, 4 drugs viz. cytarabine (Cytosar®), trabectedin (Yondelis®), eribulin mesylate (Halaven®) and the conjugated antibody brentuximab vedotin (Acentris®). are presently used in the treatment of cancer [4]. A total of about 560 anticancer compounds have so far been derived from marine organisms (invertebrates) and both sponges and cnidarians contribute to more than 85% as shown in Table 2.
Table 2Anticancer Compounds from Marine Invertebrates [5].Marine Invertebrate groupNo. of Compounds% ContributionMarine sponges27048.5Marine cnidarians21037.0Echinoderms509.0Marine molluscs203.0Tunicates152.5
Most Promising Marine Biota-Derived Anticancer Compounds for the Different Types of Human Cancer
While considering the anticancer activity of the marine biota-derived compounds, the modes of action may be cytotoxic, anti-proliferative (apoptotic and antimitotic), anti-metastatic, cancerostatic, anticarcinogenic, antileukemic or antineoplastic. The most promising anticancer compounds for the different types of human cancer are given below [6].
Human Colon Cancer
The 26-membered polyunsaturated macrolactones, derived from the obligate marine actinomycete Salinispora arenicola strain CNR-005; the cyclohexene amine derivative viz. daryamide A and the tripyrrole compounds, marineosins produced by the marine Streptomyces strain CNQ-085; the quinone, marmycin A derived from Streptomyces sp. M045 strain; and the extracts of Streptomyces strain CNR-698 have been reported to possess significant inhibitory activity against human cell line of colon adenocarcinoma HCT-116.
Human Cervical Cancer
The 16-membered macrolide viz. chalcomycin produced by the marine strain Streptomyces sp. M491 showed cytotoxic activity against human cervical cancer cell lines.
Blood Cancer
The marine bacterial strain Streptomyces sp. KORDI-3238 produces nonactin which is an antibiotic and macrotetrolide possesses significant inhibitory activity against the human K-562 erythroleukemia cell line. Further, the new anthroquinone, 1,8-dihydroxy-2-ethyl-3-methylanthraquinone derived from the extract of the marine Streptomyces sp.FX-58 cultures and the monoterpene alkaloid, altemicidin from Streptomyces sioyaensis SA-1758 showed activity against murine lymphoid L1210 leukemia. Furthermore, the indole alkaloid, streptochlorin from Streptomyces strain 04DH110 acted against human leukemia K-562 cells.
Mammary Cancer
The benzoxazole antibiotic, caboxamycin derived from Streptomyces sp. NTK 937 showed inhibitory activity against the breast carcinoma MCF7 cell line.
Hepatic Cancer
The caboxamycin of Streptomyces sp. NTK 937 also showed activity against human gastric adenocarcinoma AGS, hepatocellular carcinoma Hep G2 cell lines. The prodigiosin analogs viz. metacycloprodigiosin and undecylprodigiosin derived from the sponge Mycale plumosa exhibited anticancer activity against human hepatic carcinoma BEL-7402 cell line.
Human Skin Cancer
The macrodiolide, marinomycin A derived from by the marine bacterium, Marinispora sp. CNQ-140 exhibited inhibitory activity against human melanoma cell lines LOX IMVI, M14, SK-MEL-2, SK-MEL-5, UACC-257, and UACC-62 skin cancer.
Biogeography of Marine Invertebrate Species Yielding Anticancer Compounds
The marine invertebrate species, which yield anticancer compounds, are found distributed in many phyla such as Porifera, Cnidaria, Bryozoa, Mollusca, and Echinodermata; and Tunicata (sub-phylum of Phylum Chordata). Regarding the habitats of these species, sponges (Phylum: Porifera), bryozoans (Phylum: Bryozoa), and tunicates (Phylum: Chordata) are benthic and sessile; and sea hares and sea slugs (Phylum: Mollusca) and sea cucumbers (Phylum: Echinodermata) are benthic and slow moving. Further, it is worthy of mention here that many secondary metabolites are derived from symbiotic bacteria, like Candidatus Endobugula sertula, the symbiont in the bryozoan, Bugula neritina which produces the most important anticancer compound viz. bryostatin-1. The next source of anticancer compounds is the microorganisms consumed by these marine invertebrates. For example, the compound dolastatin 10 is produced by the cyanobacterial (blue - green alga) species Symploca sp. VP642 the food organism of the molluscan sea hare Dolabella auricularia. Similarly, the molluscan sea slug Elysia rufescens has been reported to concentrate very high concentrations of the anti-tumor compound Kahalalide F by consuming F by consuming the green algae Bryopsis pennata. Like the diversity of marine invertebrates that produce anticancer compounds, the marine habitats from which the anti-cancer chemicals have been derived are also equally diverse. For example, the habitats located near coastal areas or small islands in the tropical Pacific Ocean are known to be rich in anticancer compounds . Apart from this, the coastal (e.g. coral reefs), estuarine, and mangrove habitats are also bestowed with promising anticancer compounds. However, the open ocean or extreme environments (e.g. Antarctica) which is due to the substantial barriers associated with exploring these environments are known for the isolation of very few anticancer compounds. On the other hand, another extreme environment viz. the deep sea which is the largest environment on earth, has been reported to be a very promising location for the search of potential anti-cancer compounds. While decreasing sunlight, poor organic carbon, and increasing hydrostatic pressure are the characteristic features of these deep-sea environments, this deep sea pelagic and benthic realms are full of novel biological adaptations. Investigations made on the identified species and isolated compounds in the different depths of the dep sea from the surface and approximately 200 m have shown promising results. However, poor isolation of anticancer compounds at depths deeper than 200 m is largely due to the constraints associated with sampling and collection of promising organisms. This calls for intensive investigations associated with advanced technologies for exploring the deep sea environments for the isolation of a considerable quantity of anticancer compounds. The geographical distribution of known marine drug sources is shown in [7] Fig. (1).
Fig. (1))
Geographical distribution of known marine drug sources. (A) Each dot represents one marine source for one drug. Image credit: Dayanidhi et al., 2021 (Open access)
Major Constraints in the Development of Anticancer Drugs
The discovery of new marine biota-derived drugs is considered to be one of the most promising new directions of marine science today. Though thousands of marine biota-derived compounds have been isolated and tested over the years, only a few compounds (less than (0.5%) have entered either clinical trials or marketed as drugs. Several constraints, such as difficulties in harvesting organisms especially from the deep-sea, taxonomical identification of collected marine organisms to species level, low quantities of bioactive compounds in the extracts of marine organisms, finding adequate procedures for isolation and purification, and sustainable production of compounds are likely to slow down the entire pipeline.
CONCLUSION
The presently approved and marketed anticancer drugs are largely from the deep-sea (below 200 m) marine biota. The exploration of untapped geographical locations and overlooked taxa employing advanced technologies are the need of the hour for further efficient bioprospecting of anticancer natural products from other understudied taxa. Further, the close collaboration between inter-disciplinary experts like marine biologists (taxonomists), marine biochemists, molecular biologists, and microbiologists; and drug industries would largely help to overcome the existing constraints in the field of marine drug discovery, together with the implementation of strategies for the protection and conservation of marine biodiversity besides promoting their sustainable use.
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