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

ONAINREVIEW FOUNDATION

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 than 10 000 molecules linked to antibodies [antibody–drug conjugate (ADC)] for target-

have been reported from various marine sources, such as bryozo- ing cancerous cells. The drug ABT-414 (developed by AbbVie Inc.)

ans, sponges, sea cucumbers, sea hares, sharks, and tunicates [8]. is an antibody–drug conjugate of an epidermal growth factor

receptor (EGFR) monoclonal antibody, with marine-inspired cy-

Clinical status of marine-derived compounds totoxic monomethyl auristatin F (MMAF); it is currently undergo-

During the past 30 years, marine organisms have been extensively ing clinical trials for the treatment of glioblastoma and squamous

studied for their secondary metabolites in the search for structur- cell tumors (https://clinicaltrials.gov).

ally unique bioactive compounds [4]. There are now eight ap- BCC research highlighted that the global market value for

proved drugs on the market (Table 1) that have been isolated from marine-derived pharmaceuticals in 2011 was around US$4.8 bil-

marine organisms [10]. Spongothymidine and spongouridine were lion, and it is anticipated to reach US$8.6 billion by the end of

the first bioactive compounds isolated from marine sources. These 2016 (www.bccresearch.com/market-research/pharmaceuticals/

were isolated serendipitously from the Caribbean sponge (Cryp- marine-derived-pharma-markets-phm101a.html). In relation to

totheca crypta) during the early 1950s [4,11,12]. Today, these the discovery of anticancer drugs, the pharmaceutical value of

compounds are approved as ophthalmic antivirals in Europe (ad- MNPs ranges from US$563 billion to US$5.69 trillion [18]. There-

1

enine arabinoside, Ara-A, Vira-A ) and anticancer drugs (cytosine fore, MNP research is an interesting and exciting arena for both the

1

arabinoside, Ara-C, Cytosar-U ), respectively [11,12]. pharmaceutical care of patients and its economic impacts.

The two aforementioned drugs, along with ziconotide (v-con- The past decade was almost exclusively devoted to highlighting

1 1

otoxin, Prialt ), omega-3 acid ethyl esters (Lovaza ), eribulin the cytotoxic properties of various naturally derived compounds,

1746 www.drugdiscoverytoday.com

Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

TABLE 1

Commercially available FDA-approved drugs derived from MNPs.

Compound Class Trade name Year approved Indication

W

Cytarabine Nucleoside Cytosar-U FDA 1969 Anticancer

W

Vidarabine Nucleoside Vira-A FDA 1976 Antiviral

W

Ziconotide Peptide Prialt FDA 2004 Anticancer

W

Omega-3 acid ethyl esters Fatty acid esters Lovaza FDA 2004 Hypertriglyceridemia

W

Trabectedin Tetrahydroisoquinoline alkaloid Yondelis EMEA 2007 Anticancer

W

Eribulin mesylate Macrocyclic ketone Halaven FDA 2010 Anticancer

W

Brentuximab vedotin Antibody drug conjugate Adcetris FDA 2011 Anticancer

W

iota-Carrageenan Sulfated galactose polymers Carragelose FDA 2013 Antiviral FOUNDATION REVIEW

∗DMXBA; Reviews ∗Bryostatin; (75, 150 mg bid, Oral) (10-40 μg, IV infusion) ∗Plinabulin; (30 mg/m2, IV infusion) Schizo- ∗Plitidepsin; (Escalating doses, IV infusion) phrenia Alzhe- ∗ABT-414; (1.25, 2.0 mg/kg, IV infusion) imer’s ∗Glembatumumab vedotin (CDX-011); (Escalating doses (1.9, 2.2 mg/kg), IV infusion) ∗Lurbinectedin (PM01183); (1.0–3.0 mg/m2, IV infusion) ∗Lifastuzumab vedotin (DNIB0600A); (Escalating doses, IV infusion) ∗Pinatuzumab vedotin (DCDT-2980S); (1.8, 2.4 mg/kg, IV infusion) ∗Polatuzumab vedotin (DCDS-4501A); (1.8, 2.4 mg/kg, IV infusion) ∗GSK2857916; (20 mg/mL, IV infusion) ∗ASG-67E; (Escalating doses, IV infusion) Cancer ∗ASG-15ME; (Escalating doses, IV infusion) ∗ASG-22ME; (Escalating doses, IV infusion) ∗HuMax®-TF-ADC; (Escalating doses, IV infusion) ∗Marizomib (Salinosporamide A; NPI-0052); (0.55, 0.8 mg/m2, IV infusion) ∗MLN-0264; (1.2, 1.5, 1.8 mg/kg, IV infusion) ∗PM060184; (4 mg/m2, IV infusion) ∗SGN-CD19A (Denintuzumab mafodotin); (3 mg/kg, IV infusion) ∗SGN-LIV1A; (Escalating doses, IV infusion)

Drug Discovery Today

FIGURE 1

Marine-derived compounds at different stages of development in clinical trials, signifying the usefulness of marine natural products for treating a wide range of

disease states: 18 compounds for cancer; one for Alzheimer’s; and one for schizophrenia. Abbreviation: IV, intravenous.

as evidenced by numerous review articles. However, here we extravasation, and growth at the target organ [19]. Among these,

uniquely describe more than 20 isolated marine-derived com- cell migration represents an essential component. Any failure in

pounds for their antimigratory properties in relation to cancer this multistep process, including the requisite cell migration,

prevention. The MNPs presented in this paper have been thor- could block the entire metastatic process. From a therapeutic

oughly reviewed and have antimigratory effects in in vitro and/or in standpoint, this would, of course, be desirable.

vivo biological assays. These compounds show cancer prevention Broadly, cancer motility and/or migration (Fig. 2) can be

properties at nontoxic concentrations, as evidenced by cytotoxic- explained via two processes: directional cell extension and focal

ity assays. Thus, we provide the scientific community with adhesion [21]. During the cell extension phase, polarized cells

additional insights on the exact anti-motility mechanisms associ- induce protrusion, the lamellipodium, at the leading edge of the

ated with these MNPs. cell [21]. The actin stress fibers, being contractile in nature, provide

necessary contractility during the migration process and ultimate-

Cancer cell migration ly push the cell membrane forward [21]. Once extended, adhesion

Cell migration is considered an essential process for normal devel- molecules, such as avb5 integrin, help lamellipodium to anchor to

opment and homeostasis, but it can also contribute to certain the extracellular matrix (ECM). Actin polymerization and depo-

pathological processes, such as vascular diseases and tumor for- lymerization are tightly regulated by the Rho GTPase family and its

mation and metastasis. During metastasis, the primary tumor target, Rho-associated serine/threonine kinase (ROCK) [21]. The

tends to spread from its primary site to its preferable secondary cycle repeats with the detachment of the trailing edge of the cell

tissues or organs [19,20]. This multistep process involves a cascade from the ECM, and the cell keeps moving forward until it escapes

of events, including changes in cancer cell motility, intravasation, the primary tumor site. The cell migration property of cancer cells

www.drugdiscoverytoday.com 1747

REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

Lamellipodiu m Actin filaments Focal adhesion Trailing Leading end end Nucleus Nucleus Nucleus Reviews

ECM

ONAINREVIEW FOUNDATION Drug Discovery Today

FIGURE 2

A model of cancer cell migration on an extracelluar matrix (ECM), representing directional cell extension at the leading edge of the cell and subsequent focal

adhesion processes. The detachment of the trailing edge of the cell from the ECM is also shown.

constitutes a major challenge to cancer therapy. Furthermore, murine colon 26-L5 carcinoma cell line for its anti-invasive and

increased cell motility and invasiveness have been linked with antimigratory potential. In biological assays, this compound sup-

the acquisition of epithelial–mesenchymal transition (EMT) fea- pressed both the invasion (IC50 1.0 mg/ml) and migration (IC50

tures via inchoate cancer cells [22]. Although the EMT process is 0.63 mg/ml) of cancer cells without showing any cytotoxicity in a

integral to wound healing and overall development, it also con- dose-dependent manner [27]. It also inhibited the proteolytic

tributes to cancer progression. Recent studies have suggested that activities of MMP2 and MMP9 with IC50 of 0.46 and 0.60 mg/

key transcription factors, including the basic helix–loop–helix, ml, respectively. At the tested concentrations, BU-4664L showed

zinc-finger E-box-binding (ZEB), and SNAIL, have a critical role no effects on cell proliferation; however, at a concentration of

in mediating this switch in cell differentiation from polarized 7.8 mg/ml, 50% growth inhibition was recorded in the murine

epithelial to motile mesenchymal cells [22]. Several signaling colon 26-L5 cells.

pathways (and signaling crosstalk) aid in the overall EMT process, The above results demonstrated the potential of BU-4664L for

with the transforming growth factor b (TGFb) family being the controlling crucial cancer cell migration and extracellular matrix

most predominant. TGFb has been found to induce EMT through degradation steps. Furthermore, BU-4664L inhibited the migration

both SMAD-mediated changes in gene expression and nonSMAD- (IC50 0.43 mg/ml) of human umbilical vein endothelial cells

mediated pathways [22]. Various marine-derived natural products (HUVEC) in an in vitro vascular organization model using fuma-

have been proven effective in inhibiting the cell motility and/or gillin as a control, which suggested antiangiogenic activity [27].

migration in several cancer cell lines. Here, we describe various Several studies reported its mechanism of action to be associated

isolated MNPs that have shown antimigratory effects against with the inhibition of the Ras, Raf, and K-Ras–mitogen-activated

various cancer cells. protein kinase (MAPK) signaling pathways and peripheral benzo-

diazepine receptors [28]. The compound was active against several

Marine-derived cancer cell migration inhibitors glioma, pancreatic, and breast cancers, especially triple negative

BU-4664L (diazepinomicin) cell lines, as well as prostate cancer. Therefore, the role of BU-4664L

BU-4664L (Fig. 3) was isolated from deep-sea water in Toyama Bay in cell migration inhibition can also be explained by targeting the

from the culture extract of Micromonospora sp. [23]. The isolation motility of cells, which are regulated by Ras via the phosphoinosi-

of this compound was also reported from the extract of a microbial tide 3-kinase (PI3K) pathway. A Phase II clinical trial was conducted

culture associated with a marine ascidian, indicating the presence in 2008 by Thallion Pharmaceuticals in patients with glioblastoma

of this bacterial strain in a wide-ranging marine environment [24]. multiform. However, it was quickly terminated because of the lack

BU-4664L was recognized as a unique compound among the of efficacy, which indicated the need for further optimization and

known microbial metabolites because it contains a rare dibenzo- pharmacokinetic studies before reuse in future clinical trials. BU-

diazepinone heterocyclic core and a farnesyl carbon chain [25]. 4664L did provide a new scaffold entity that pinpointed an impor-

The biosynthetic pathway of BU-4664L is complex and is thought tant molecular target for future development.

to involve more than 40 enzymes [26]. BU-4664L was tested in the

OH HO HO OH

OH O OH O OH N O O OH O OH NH O OH HO OH O O OH OH

Drug Discovery Today Drug Discovery Today

FIGURE 3 FIGURE 4

Chemical structure of BU-4664L isolated from Micromonospora sp. Chemical structure of dieckol isolated from Ecklonia cava.

1748 www.drugdiscoverytoday.com

Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

Dieckol respectively. Frondoside A reduced the cellular migration of the

Dieckol (Fig. 4) was isolated from the marine brown algae Ecklonia tested cell line at both concentrations (0.1 and 1 mM) and in a

cava [29,30]. In Korea and Japan, dieckol is one of the major time-dependent (2–6 h) manner without affecting the viability of

polyphenolic components of an edible alga that is popular as a the cancer cells [33]. The reported IC50 value of frondoside against

food ingredient for human consumption as well as for animal feed MDA-MB-231 cells was 2.5 mM in a CellTiter-Glo luminescent cell

supplements. Structurally, dieckol is a phloroglucinol belonging viability assay, which was based on quantification of ATP. Simi-

to the phlorotannins class of condensed tannins. This compound larly, low concentrations of frondoside A (0.01–0.5 mM) inhibited

was extensively tested against human fibrosarcoma cells (HT1080) the invasion of breast cancer cells through matrigel, without

and was identified to suppress their migration and invasion [31]. affecting cell viability [33]. Furthermore, in vivo studies in athymic

The cell viability of HT1080 cells in the MTT assay was not affected mice showed a strong reduction in growth of MDA-MB-231 tumor

by dieckol at concentrations below 50 mg/ml; therefore, both the xenografts when 100 mg/kg of frondoside A was given daily via

wound-healing scratch and matrigel invasion assays, respectively, intraperitoneal (i.p.) injection. It was also reported that frondoside FOUNDATION REVIEW

were used for testing the migration and invasion inhibitory po- A was able to inhibit the migration of cancer cells in response to

tential of this compound at 25 mg/ml. Migration and invasion of prostaglandin E2 (PGE2) or EP4-specific ligand PGE1-OH. There-

dieckol-treated cells were reduced to approximately 50% and 19%, fore, it was proposed that frondoside A serves as a functional

Reviews

respectively, of the levels of the control cells. In addition, the antagonist of the PGE receptors EP2 and EP4 [34]. Further studies

adhesion of HT1080 cells to the fibronectin-coated plate was reported the invasion and migration inhibitory effects of frondo-

significantly decreased with treatment of 25 mg/ml of dieckol in side A in 12-O-tetra-decanoylphorbol-13-acetate (TPA)-stimulated

the cell adhesion assay. MDA-MB-231 cells [35]. Frondoside A reduced the expression of

The abovementioned results suggested that dieckol has the MMP-9 in TPA-stimulated breast cancer cells, blocked the activa-

ability to regulate the intracellular signaling cascades involved in tion of transcription factors activator protein 1 (AP-1) and nuclear

migration, invasion, and adhesion. The reported mechanism of factor (NF)-kB, and blocked various signaling pathways, including

action suggested a possible intracellular reactive oxygen species PI3K/Akt, ERK1/2, and p38 MAPK. These results highlighted the

(ROS) scavenging effect that contributed to the migration of cancer potential of frondoside A to control and prevent TNBC metastasis.

cells and invasion inhibitory effects. Dieckol treatment also re-

duced Rac1 activation and focal adhesion kinase (FAK)-Src-p130Cas Fucoidan

complex formation, and overall expression and phosphorylation of Fucoidan, a sulfated polysaccharide (Fig. 6), was first extracted in

FAK as well as the expression of matrix metalloproteinase (MMP)-2, 1913 from marine brown algae [36]. It is also known as fucan,

9, and 13 in HT1080 cells [31]. sulfated fucan, or fucosan [37]. Structurally, it is a heparin-like

polysaccharide with an a-1,3-backbone [38]. The invasion and

Frondoside A migration inhibitory capacities of the human TNBC MDA-MB-

Frondoside A (Fig. 5) is a marine triterpene glycoside isolated from 231 and 4T1 (mouse breast adenocarcinoma) cells were examined

1

the Atlantic edible sea cucumber Cucumaria frondosa [32]. Over- in the presence of fucoidan (100 mg/ml) using the Transwell

the-counter dried sea cucumber extracts are sold in the USA and assay [38]. The results indicated significant inhibition of invasion

Canada as dietary supplements. Frondoside A was tested in vitro (decreased by approximately 50% in both cell lines) and migration

using human triple negative breast cancer (TNBC) MDA-MB-231 (reduced by >30% and 50%, respectively) of breast cancer cells in

cells for its inhibition of migration and invasion capacities via the MDA-MB-231 and 4T1 cell lines. In addition, in vivo studies

a classic wound-healing model and a matrigel invasion assay, using female Balb/c mice demonstrated the effectiveness of

O O H OAc

O H O OH

CH2OH NaO3SO O O OMe O O O HO O OH OH HO OH OO OH HO OH Drug Discovery Today

FIGURE 5

Chemical structure of frondoside A isolated from Cucumaria frondosa.

www.drugdiscoverytoday.com 1749

REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

– –O SO O3SO –O SO –O SO 3 O – 3 3 O O3SO O O HO O O O OH O OH O OH OH OH OSO – CH 3 CH3

Reviews 3 CH3 CH3 CH3 Drug Discovery Today ONAINREVIEW FOUNDATION

FIGURE 6

Chemical structure of fucoidan isolated from marine brown algae.

fucoidan (0.25 mg/mice) in reducing tumor volume as well as the developed as a therapeutic agent specifically geared to disrupt the

formation of metastatic lung nodules in a 4T1 xenografted mouse tumor actin cytoskeleton without affecting normal cells.

model. Furthermore, studies showed that fucoidan acts via an

ubiquitin-dependent proteasome-mediated degradation pathway; Heteronemin

therefore, it directly affects the TGF receptors (TGFR) Smad/Snail, Heteronemin (Fig. 8) is a scalarin-type sesterterpene isolated from

Twist, and Slug, and, hence, targets the EMT axes. the sponge Heteronema erecta [41]. Heteronemin was assessed for its

ability to prevent tumor cell intravasation through the lymph-

Geodiamolide H endothelial barrier in a 3D cell culture model [42]. Estrogen

Geodiamolide H (Fig. 7) is a cyclodepsipeptide that was isolated receptor (ER)-positive human breast cancer cells MCF-7 were

from the Brazilian marine sponge Geodia corticostylifera [39]. Geo- placed on lymph-endothelial cell (LEC) monolayers [42]. The

diamolide H was tested against the human mammary Hs578T cell tumor cell spheroids generated ‘circular chemorepellent-induced

line to investigate its effect on the invasion and migration of defects’ (CCIDs) in the LEC monolayer [42]. 12(S)-Hydroxyeico-

cancer cells [40]. This compound inhibited both the invasion satetraenoic acid (12(S)-HETE) and NF-kB activities were major

and migration of these cells in a dose-dependent manner, as features of the induction of CCIDs, which are entry gates for tumor

indicated by time-lapse microscopy, a Transwell invasion assay, emboli intravasating the vasculature [42]. Heteronemin (at 5 mM

and a scratch-wound closure assay. In an established scratch- treatment) prevented directional movement of LECs and subse-

wound closure assay, geodiamolide H at 10, 20, and 120 nM quently inhibited MCF-7 spheroid-induced CCID formation, indi-

concentrations afforded increments in the cell-free area to at least cating its potential to prevent lymph node metastasis.

75% compared with the control (20%). Similarly, the results of the Furthermore, Western blot analyses, NF-kB reporter, EROD, SELE,

matrigel-coated Boyden chamber invasion assay showed a 30% 12(S)-HETE, and adhesion assays were performed to investigate the

reduction in the invasion rate of Hs578T cells treated with 120 nM properties of heteronemin. Heteronemin also suppressed 12(S)-

geodiamolide H. In addition, microscopic analysis of geodiamo- HETE-induced expression of paxillin, the EMT marker and direc-

lide H-treated cells showed reversal of malignant phenotypic tional cell migration regulator. Heteronemin also inhibited the

characteristics to polarized spheroid-like structures. It was pro- activity of CYP1A1, which promoted CCID formation, indicating

posed that the actin cytoskeleton modification is the primary the ability of heteronemin to inhibit breast cancer intravasation

mechanism by which geodiamolide H exerts its effect. Geodiamo- [42].

lide H-induced actin disassembly is selective to Hs578T cancer cells

and does not affect MCF-10A, nontumorigenic human mammary Latrunculins

epithelial cells; therefore, geodiamolide H has the potential to be Latrunculin A and B (Fig. 9) are marine-derived macrolides isolated

from the Red Sea sponge Negombata magnifica [43]. Both latrun-

culins act by disrupting the organization of the cell microfilaments

OH

[44]. It has also been reported that latrunculins form a 1:1 complex

with G-actin and thereby can disrupt its polymerization [44,45].

O O HN O O I O OH O N O HO H O

NH H H O

O H

Drug Discovery Today Drug Discovery Today

FIGURE 7 FIGURE 8

Chemical structure of geodiamolide H isolated from Geodia corticostylifera. Chemical structure of heteronemin isolated from Heteronema erecta.

1750 www.drugdiscoverytoday.com

Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

O O

O O N H O O N H HO HO H NH HN S HN S 2 Drug Discovery Today O O

FIGURE 10

Latrunculin A Latrunculin B Chemical structure of motuporamine C isolated from Xestospongia exigua. Drug Discovery Today FOUNDATION REVIEW O

FIGURE 9 OH

Chemical structures of latrunculins A and B isolated from Negombata H O H OH magnifica. H Reviews O H OH O

HH O

Unlike geodiamolide H, latrunculins disrupt actin microfilaments O

O H

in both cancerous and noncancerous cells [40]. Interestingly, their H

binding to cytoskeleton actin monomers is reversible [44]. Latrun-

culins have the common scaffold of a 16- or 14-membered macro- Pachycladin A Pachycladin D

lactone ring fused with a tetrahydropyran ring, to which a rare Drug Discovery Today

thiazolidinon-2-yl moiety is attached. Total syntheses of latrun-

FIGURE 11

culins A and B were reported independently by several groups

[46–48]. Chemical structures of pachycladins A and D isolated from Cladiella

pachyclados.

The antimigratory activity of latrunculins was explored only

recently. El Sayed et al. revisited the Red Sea sponge Negombata

magnifica and isolated both latrunculins A and B along with other

new latrunculins [49–51]. Latrunculins A and B displayed potent studies have suggested that motuporamine C (Fig. 10) at 5 mM

antimigratory activity against highly metastatic human prostate impairs actin-mediated membrane ruffling at the leading edge of

+

cancer PC-3M-CT cells and murine brain-metastatic melanoma lamellae in TNBC MDA-MB-231 cells, prostate carcinoma PC-3

B16B15b cells, respectively [49,50]. Similarly, latrunculin A cells, and glioma U-251 cells [54]. The total synthesis of motupor-

1

showed potent anti-invasive activities (Cultrex BME cell invasion amine C was reported after its isolation, which provided a platform

assay) in the TNBC MDA-MB-231 cell line in a dose-dependent to develop its preliminary structure–activity relation [55,56].

manner, with concentrations ranging from 0.1 mM to 1 mM. To

assess the cytotoxicity of this compound, a routinely used MTT Pachycladins

assay was performed, and the reported results suggested nontoxic Pachycladins A–E were isolated from the Red Sea soft coral Cladiella

behavior at concentrations of 1.0 mM [51]. The antimigratory pachyclados [57]. Among the isolated eunicellin diterpenes, pachy-

effects of latrunculin B were accessed using two established assays: cladins A and D (Fig. 11) exerted the most potent antimigratory

Boyden’s chamber and wound-healing assays. The results of these activities when tested against prostate cancer PC-3 cells [57]. The

assays indicated a significant reduction in the migration of reported IC50 values of pachycladins A and D were 5 mM and

B16B15b cells at a 1 mM concentration [49]. Additional unknown 75 mM, respectively, in the wound-healing assay. These com-

macromolecular target(s) were hypothesized for their biological pounds did not affect the proliferation or viability of PC-3 cells;

activities rather than for their microfilament–actin disruption therefore, the unknown, yet molecular, target(s) of pachycladins

pathways [50,51]. is/are proposed as one or more of the important cell migration

steps during the process of cancer metastasis [57,58].

Motuporamines

Various motuporamines (A–I), which are macrocyclic alkaloids, Penicillivinacine and terretrione A

were isolated from the tropical sponge Xestospongia exigua [52,53]. Penicillivinacine and terretrione A (Fig. 12) are marine-derived

Motuporamines contain a unique spermidine-like substructure alkaloids that were recently isolated from the fungus Penicillium

and are thought to be biogenetically derived from basic building vinaceum [59,60]. The host organism carrying the fungus, the

blocks, such as ammonia, acrolein, and a long-chain dialdehyde marine sponge Hyrtios erectus, was collected from the Red Sea coast

[52]. Motuporamines were reported to inhibit cell motility in in Yanbu, western Saudi Arabia. Both penicillivinacine (IC50 value

monolayer cultures of MDA-MB 231, PC-3, and U-251 cells at a 18.4 mM) and terretrione A (IC50 value 17.7 mM) were found to

concentration of 5 mM in the wound-healing assay [54]. In addi- inhibit the migration of TNBC MDA-MB-231 cells significantly in

tion, anti-invasive assay results revealed that motuporamine C was vitro using a wound-healing assay model. Given its recent isola-

slightly less active than strongylophorine-26 (described below) tion, the molecular mechanism of penicillivinacine has not yet

when tested using the matrigel invasion assay. Detailed biological been fully examined, and future mechanistic studies are needed to

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REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

obtained using this assay: penitrem A, 8.7; penitrem B, 10.3; and

O

H penitrem D, 9.2. Their mechanism of action was proposed to target

O N O

N the Wnt signaling-b-catenin pathway in the TNBC cell line MDA-

H

HN MB-231 [61]. Detailed pharmacological evaluation will help eluci-

O N

OH H date the exact mechanism of action of this class of compound

O O

Reviews given the relatively recent reporting of the anti-invasive and

antimigratory activities of penitrem. The chemically simplified

Penicillivinacine Terretrione A

biosynthetic precursors of penitrem, paspaline and emindole SB Drug Discovery Today

ONAINREVIEW FOUNDATION

(Fig. 13), also showed potent anti-invasive and antimigratory

FIGURE 12 activities against breast cancer cell lines. The total synthesis of

Chemical structures of penicillivinacine and terretrione A isolated from penitrem D has been reported; however, a complete synthetic

Penicillium vinaceum. scheme for penitrems A and B is elusive because of their architec-

turally complex structures [62,63].

provide insights into this new alkaloid with its novel carbon

skeleton. Phenylmethylene hydantoins

The (Z)-5-(4-hydroxybenzylidene) hydantoin (PMH) (Fig. 14) was

Penitrems isolated from the marine Red Sea sponge Hemimycale arabica [64].

Penitrems A, B, and D (Fig. 13) are marine-derived alkaloids This shallow-water sponge, belonging to the family Mycalidae, is

isolated from a fungal extract of Penicillium commune [61]. This abundant along the Egyptian Red Sea coast. The results of in vitro

+

fungus was cultured from marine sponges and sediment specimens studies conducted on the PC-3M-CT human prostate cancer cell

that were collected from the Kuwaiti Arab Gulf coast. Structurally, line suggested that PMH augments the cell–cell adhesion of cancer

penitrems comprise a cyclic diterpene skeleton with an indole ring cells and thereby can stabilize junctional complexes [65,66]. In-

system, and are well known as selective antagonists to the calcium- terestingly, PMH and its synthetic analog, (Z)-5-[4-(ethylthio)ben-

dependent potassium channels (BK, Maxi-K channels). They are zylidene] hydantoin (Seth), also reversed the effect of calcitonin,

also known tremorgen inducers in animals. Penitrems A, B, and D known to promote prostate cancer metastasis by reducing cell–cell

were evaluated for their anti-invasive and antimigratory activities adhesion on junctional disruptions and metastases. Moreover,

against human breast cancer cells MDA-MB-231 [61]. At subtoxic PMH significantly increased the transepithelial resistance and

concentrations (15 mM), these compounds showed significant decreased the paracellular permeability of polarized PC-3M cells,

1

inhibition of cancer cell invasion in the Cultrex BME cell inva- suggesting the beneficial effect of this compound on tight junc-

sion assay kit. The highest activity was seen with penitrem A, tions. Furthermore, both compounds decreased the expression of

which inhibited >75% of the cell invasion, followed by penitrems CD44 total mRNA as well as CD44v7-10 protein in prostate cancer

B and D, with approximately 40% and 50% inhibition, respective- cells [67]. b-Catenin and 1b-integrin levels were also reported to

+

ly. The directional cell migration inhibitory potential was assessed be lowered in PC-3M-CT cells in the presence of PMH and

using a wound-healing assay. The IC50 values in the mM range were Seth [65,67]. Both compounds showed prominent antimetastatic

H H H H O H O H R2 H O OH OH R N OH N OH 1 H H O O H H

R1 R2

Penitrem A Cl OH Penitrem D Penitrem B H H

H H

N N H H

O OH H H OH

Paspaline Emindole SB

Drug Discovery Today

FIGURE 13

Chemical structures of penitrems A, B, and D isolated from Penicillium commune. Paspaline and emindole SB are biosynthetic precursors of penitrem.

1752 www.drugdiscoverytoday.com

Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

O NH HN O O O

HN HN HO NH S NH

O O F (Z)-5-(4-hydroxybenzyl- (Z)-5-(4-(ethylthio)benzylidene)- (Z)-5-((4'-fluorobiphenyl- idene) hydantoin hydantoin 4-yl)-methylene) hydantoin

Drug Discovery Today FOUNDATION REVIEW

FIGURE 14

Chemical structure of phenylmethylene hydantoin isolated from Hemimycale arabica and related synthetic analogs.

Reviews

activity, without apparent cytotoxic effects, in the orthotopic product containing a 1,2,4-oxadiazole ring system [73,74]. Phi-

xenograft of PC-3M cells in a nude moue model (i.p. dose: dianidine A was tested using the rat pituitary adenoma cell line

PMH, 5 mg/g body weight/day; Seth, 1 mg/g body weight/day), GH4C1 [75]. To rule out the possibility of nonspecific toxic effects

which inhibited tumor growth and the formation of tumor micro- of this compound, the MTT reduction assay was used to evaluate

metastases in distant organs. They also showed potent antimeta- the cytotoxicity. The increasing doses of phidianidine A (1, 10, and

static activity in the LPB-Tag transgenic mice model, reducing the 50 mM) showed no effect on cell viability in both the CXCR4-

growth of primary tumors and their metastasis in reproductive expressing and downregulated cells. The results of this study

organs, decreasing morbidity, and increasing the survival average reported the inhibition of CXCL12-induced DNA synthesis, and

of the mice [64,65]. ERK1/2 activation. The CXCR4, or chemokine receptor, is known

Further studies on PC-3 prostate cancer cells and MDA-MB-231 to control tumor cell migration and, therefore, to help cancer

TNBC cells validated the anti-invasive and antimigratory proper- cells metastasize. Phidianidine A (50 mM) significantly reduced

ties of PMH and related synthetic analogs [68–70]. In breast cancer CXCL12-induced migration in the GH4C1 cell line. This migra-

in vitro and in vivo assay models, the PMH-inspired analog (Z)-5- tion assay was conducted using a 24-well HTS Fluoro Blok insert

0

[(4 -fluorobiphenyl-4-yl)-methylene] hydantoin potently sup- system in fluorescence experiments, with or without a 50 nM dose

pressed the expression of the total levels of c-Met and FAK, with of CXCL12 as a chemoattractant molecule. Total synthesis of this

subsequent reduction in their phosphorylated (activated) levels in unique bromoindole-guanidine-containing phidianidine A has

MDA-MB-231 cells [70]. It also inhibited breast tumor kinase (Brk), been reported [73,74].

0

paxillin, and Rac1 phosphorylation. In addition, (Z)-5-[(4 -fluor-

obiphenyl-4-yl)-methylene] hydantoin reduced breast tumor Sarcophine

growth in a nude mouse xenograft model using MDA-MB-231/ Sarcophine (Fig. 16) is a marine-derived cembranoid first isolated

GFP cells and suppressed Ki-67, CD31, p-Brk, and p-FAK expression by Kashman and coworkers from the Red Sea soft coral Sarcophyton

in tumor samples [70]. Thus, the PMH entity was proposed as a glaucum during the early 1970s [76]. In general, cembranoids are a

potential lead for the control of invasive breast malignancies. PMH class of diterpenes with a 14-membered macrocyclic ring [77].

and related synthetic analogs have also shown potent glycogen Sarcophine showed potent dose-dependent inhibition of the mi-

synthase kinase-3b inhibitory activity with an IC50 range of gration of highly metastatic mouse melanoma B16B15b cells in a

4–20 mM [71]. Total single-step synthesis of this compound has wound-healing assay when tested at 1, 10, and 100 mM concen-

been reported in numerous studies [64]. trations [78]. Additionally, sarcophine and its related analogs

significantly inhibited the migration of highly metastatic MDA-

Phidianidine A MB-231 breast cancer cells and PC-3 prostate cancer cells in in vitro

Phidianidine A (Fig. 15) is an indole alkaloid isolated from the wound-healing assays [79]. The reported IC50 values of the related

marine shell-less opisthobranch mollusk Phidiana militaris, which sarcophine analogs ranged from 4.8 mM to 30.0 mM in MDA-MB-

was collected from the coast of Hainan Island along the South 231 cells and from 15.5 mM to 24.3 mM in PC-3 cells. The cytotox-

China Sea [72]. This compound is believed to be the first natural icity evaluations that used the MTT assay revealed no toxicity

H O N N H O Br H O N N O N NH2 H HN Drug Discovery Today

Drug Discovery Today

FIGURE 15 FIGURE 16

Chemical structure of phidianidine A isolated from Phidiana militaris. Chemical structure of sarcophine isolated from Sarcophyton glaucum.

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REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

H O N O N NH2 N NH H OH CH Br H 2 N NH O H O O NH2 Reviews NH N Drug Discovery Today

FIGURE 18

ONAINREVIEW FOUNDATION Br

Chemical structure of sinulariolide isolated from Sinularia flexibilis. Drug Discovery Today Sinulariolide

FIGURE 17

Sinulariolide (Fig. 18) is a cembranoid-type diterpene isolated from

Chemical structure of sceptrin isolated from Agelas sceptrum.

the soft coral Sinularia flexibilis [85]. Several derivatives of sinular-

iolide were also reported from other Sinularia species. Recently,

issues at the tested doses. Further mechanistic investigation of the sinulariolide was investigated for its cancer cell migration inhibi-

scaffold of sarcophine will help to identify its exact molecular tory properties in human hepatocellular carcinoma cells (HA22T)

target(s). Numerous attempts have been made toward the total using a wound-healing assay [86]. In addition to inhibiting cell

synthesis of sarcophine [80,81]. migration, sinulariolide also showed inhibition of the invasive

effects of HA22T cells in a concentration-dependent manner

Sceptrin (2–8 mg/ml). At a concentration of 8 mg/ml, sinulariolide-treated

Sceptrin (Fig. 17) is a bromopyrrole imidazole alkaloid produced cells for 24- and 48-h time points showed 50% and 78% migration

by various marine sponges that recently showed inhibition inhibition and 80% and 84% invasion inhibition, respectively.

toward cell motility in a variety of cancer cell lines, including The invasion assay was conducted using standard transwell cham-

cells of the human cervical cancer HeLa, metastatic TNBC MDA- bers coated with matrigel. No apparent cytotoxic effects of sinu-

MB-231 cells, and lung cancer A549 cells [21]. The cell motility lariolide were noted at the tested concentrations. Further

inhibition was assessed using the cell motility HitKit manufac- pharmacological evaluation of sinulariolide-treated HA22T cells

tured by Cellomics. The dose-dependent experiment conducted revealed a reduction in MMP-2, MMP-9, and urokinase-type plas-

in the presence of 10 ng/ml HGF (cell motility inducer) on HeLa minogen activator (uPA) expression levels [86]. Various signaling

cells demonstrated the maximum inhibitory effect of sceptrin at pathways, including PI3K/Akt, MAPKs, and FAK/GRB2, were also

a concentration of 50 mM (IC50 value 15 mM). Similar results reported as suppressed, which suggested a potential role of sinu-

were obtained with 40 mM of sceptrin in A549 cells treated with lariolide in altering hepatoma cell metastasis.

10 ng/ml of HGF. Interestingly, no external mitogen was added

to the MDA-MB-231 cells (to exhibit high baseline cellular Sinulodurins

motility), yet the 40 mM sceptrin dose showed potent inhibition Sinulodurin A and B (Fig. 19) were isolated from the Palau soft

of the motility of cells. Sceptrin did not show any cytotoxic coral Sinularia dura [87]. These two diterpenes inhibited the inva-

+

effects; this was assessed using both an established cell prolifer- sion of highly metastatic prostate cancer PC-3M-CT cells in the

ation assay (positive control, 5 nM aphidicolin) and a cell death 3D-spheroid disaggregation assay model. Both sinulodurin A and B

assay (positive control, 5 nM staurosporine) in the studied cell effectively decreased the disaggregation and cell migration of

lines [21]. cancer cells in a dose-dependent manner when tested at 25, 50,

Sceptrin is believed to target a central process of the cell

motility machinery because both random and factor-induced

migration steps were found to be impaired [21]. Detailed time- R

lapse confocal microscopy results showed that sceptrin-treated 2

1

cells did not block lamellipodia formation but impacted the

H H

directional movement of the cells, ultimately pulling back the

protrused lamellipodia. The source of contractile force generation

in the cells may be impaired with treatment with sceptrin. This

AcO O

was later proven by using isothermal titration calorimetry, which

proved the ability of sceptrin to bind at the monomeric actin

(Kd value of 19.2 0.2 mM). Future studies will help reveal other

potential mechanisms of this unique compound beyond its bind-

ing to actin [21]. This compound was first isolated from the

Sinulodurin A (R = OAc)

sponge Agelas sceptrum [82]. In 2004, the total synthesis of scep- Sinulodurin B (R = H)

trin was reported, which opened the door for an extensive evalu-

Drug Discovery Today

ation of its potential in medicine [83]. In 2007, a refined synthetic

route was designed to deliver multigram quantities of this chemi-

FIGURE 19

cally and pharmacophorically unique bioactive natural product Chemical structures of sinulodurin A and sinulodurin B isolated from Sinularia [84]. dura.

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Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

O Cl OH R O O Cl O A H H OH O H H OH H H D H B H OH H H H C H H HO

HO HO H

OH

Sipholenol A (R: OH) Sipholenol E Sipholenol A-4-O-3 ′,4′- Sipholenone A (R: = O) dichlorobenzoate (SPA)

Drug Discovery Today FOUNDATION REVIEW

FIGURE 20

0 0

Chemical structures of sipholenol A, sipholenol E, and sipholenone A isolated from Callyspongia siphonella, and the semisynthetic analog sipholenol A-4-O-3 ,4 -

dichlorobenzoate. Reviews

100, and 200 mM. However, sinulodurin A was more active against elimination of rings C and D [(5,3,0)bicyclodecane system] [90].

prostate cancer cell migration inhibition than was sinulodurin B, This structure simplification proposed the possibility of future

suggesting the importance of the C-2 acetoxy group for the activity synthesis of the new active entities and further demonstrated

of this class [87]. The mechanistic studies on sinulodurins are the potential of MNPs for the discovery of novel scaffolds for

currently lacking; therefore, future biological evaluation is need- the control and management of metastatic breast cancer [90,91].

ed, which might provide insights regarding the exact mechanism

of action of these compounds. Strongylophorine

Strongylophorine-26 (Fig. 21) is a unique meroditerpenoid isolat-

Sipholanes ed from the marine sponge Petrosia (Strongylophora) corticata,

Sipholanes (Fig. 20) are marine-derived products isolated from the which was collected from Papua New Guinea [92]. The uniqueness

Red Sea sponge Callyspongia siphonella [88]. These triterpenes have of this compound lies in its ability to inhibit the invasiveness of

a perhydrobenzoxepine (rings A and B) and a bicyclodecane (rings the TNBC MDA-MB-231 cells (tested concentration range 0.5–

C and D) conjugated ring system [89]. Sipholenol A, sipholenol E, 2.5 mg/ml) via a distinctive mechanism of action [93]. Additional

and sipholenone A showed potent antimigratory activity, with testing in an in vitro wound-healing assay demonstrated the cell

IC50 values in the mid-mM range (28–37 mM), when tested on migration inhibitory potential of strongylophorine. At the tested

highly metastatic MDA-MB-231 breast cancer cells using a concentrations, strongylophorine-26 caused no detectable cyto-

wound-healing assay [88,89]. Sipholanes have been found to be toxicity (IC50 = 5 mg/ml) during a 24-h treatment period. Interest-

P-glycoprotein (P-gp) modulators, and also inhibit the phosphor- ingly, strongylophorine-26 induced a decrease in actin stress fibers

ylation of breast tumor kinase (Brk), a potent inducer of migration in MDA-MB-231 cells, which is in contrast to other inhibitors of

0 0

[89,90]. Sipholenol A-4-O-3 ,4 -dichlorobenzoate (SPA) suppressed cell migration, such as fumagillin, TNP-470, endostatin, dihydro-

the human breast cancer cells MDA-MB-231, MCF-7, BT-474, and motuporamine C, thronbospondin-1, and EMAP II, all of which

T-47D migration and invasion, and decreased Brk and FAK activa- act via the induction of actin stress fibers [93,94]. This discovery

tion in a dose-dependent manner (5–20 mM SPA treatment). This also showed that stabilization of actin stress fibers is not the only

was one of the few small-molecule examples in the literature that mechanism for the pharmacological inhibition of cell migration

uniquely targeted Brk, a mediator of cancer cell phenotypes that is [93]. In addition, strongylophorine-26 increased the size and

important for proliferation, survival, and migration. This com- number of focal adhesion points and induced a dense meshwork

pound showed no toxicity to nontumorigenic human mammary of actin filaments around the cell periphery. Various analogs of

epithelial cells MCF-10A at concentrations equal to their IC50 strongylophorine-26 have also been synthesized, and their biolog-

values or higher in the MTT cytotoxicity assay. Molecular model- ical characterizations revealed the importance of the lactone ring

ing suggested a unique fitting at the FERM domain of FAK, inhibit-

ing the main autophosphorylation site, Y397, which was further

O

confirmed by Western blot analysis [91]. Most known small-mol-

OH

ecule FAK inhibitors target the kinase domain, creating several off- O

target effects. In vivo, SPA treatment suppressed breast tumor

O O

growth and Ki-67, CD31, p-Brk, and p-FAK expression in ortho- H

O

topic breast cancer xenograft in nude mice, suggesting good

H

potential for its therapeutic use to control invasive breast cancer

Drug Discovery Today

[91]. Pharmacophore modeling studies provided evidence for the

future design of novel antimigratory compounds based on a

FIGURE 21

simplified sipholane structure, with rings A and B (perhydroben- Chemical structure of strongylophorine-26 isolated from Petrosia

zoxepine), connected to the substituted aromatic esters, with the (Strongylophora) corticata.

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REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

OH showed significant inhibition in invasion of cells compared with

O O

H the PMH analog Seth positive control. Subereamolline A demon-

N

N strated no toxicity at the tested concentrations, as evidenced by

HN

the MTT assay. The total synthesis of subereamolline A has been

O O

reported recently, which will aid in identifying its exact molecular

NH

Reviews mechanism and its use as a parent scaffold for the development of

N

more potent cancer cell migration inhibitors [98]. O O

ONAINREVIEW FOUNDATION N

HN Sungsanpin

N Sungsanpin (Fig. 24) is a 15-amino acid lasso peptide identified

O H O

during the search for novel bioactive molecules from deep-sea

NH sediments. The sediment was collected off the coast of Sungsanpo

on Jeju Island, Korea at a depth of 138 m [99]. Recently, there has

been increased scientific interest in deep-sea habitats because they

Drug Discovery Today are the least explored; therefore, they have immense potential for

the discovery of new compounds. This peptide was discovered

FIGURE 22

from one of the actinobacterial strains, Streptomyces sp., which was

Chemical structure of stylissamide X isolated from Stylissa sp.

isolated from the sediment. Sungsanpin showed potent anti-inva-

sive activity in the human lung cancer cell line A549 [99]. For

and the methoxy-substituted quinone moiety as essential phar- determining the in vitro invasiveness of cells in the presence of

macophoric elements [94]. sungsanpin, a cell invasion assay kit (Chemicon) was used. The

obtained results suggested a 25% and 47% inhibition in terms of

Stylissamide X the invading capacity of cells from the upper chamber to the lower

Stylissamide X (Fig. 22) is a proline-rich cyclic octapeptide isolated chamber when exposed to 5 and 50 mM sungsanpin, respectively.

from an Indonesian marine sponge Stylissa sp. [95]. This com- The cytotoxicity of this compound was examined using the cell

pound was tested against HeLa adenocarcinoma cells for its anti- counting kit-8 (Dojindo Laboratories), which showed no cellular

migratory potential in both a wound-healing assay and a damage at concentrations up to 50 mM. In mechanistic studies,

chemotaxicell chamber assay. Stylissamide X potently inhibited sungsanpin significantly increased the TIMP-1 and TIMP-2 mRNA

the migration of these cells in the low micromolar range (0.1– levels in a concentration-dependent manner (0–50 mM), possibly

10 mM), without significantly affecting the viability of cells, and explaining the decrement in the invasiveness of sungsanpin-trea-

was assessed using the MTT assay. Further biological evaluation of ted A549 cells [99].

this peptide-based compound will provide insights into its exact

mechanism of action. Total synthesis of stylissamide X was re- Waixenicin A

cently reported [96]. Waixenicin A (Fig. 25) is a xenicin diterpenoid that was first

isolated by Coval et al. from the marine soft coral Anthelia edmond-

Subereamolline A soni [100]. Waixenicin A was found to inhibit transient receptor

Subereamolline A (Fig. 23) is a bromotyrosine alkaloid that was potential melastatin 7 (TRPM7) ion channels rather potently and

isolated from the Red Sea verongid sponge Suberea mollis and in a dose-dependent manner, with an IC50 of the maximal slope of

collected from Hurghada on the Egyptian Red Sea coast [97]. This the magnesium ion quench of 12 mM [101]. TRPM7 is known to

compound showed significant anti-invasive and antimigratory regulate the migration of highly tumorigenic human nasopharyn-

activities when tested against the metastatic human TNBC cell geal carcinoma cells 5-8F, as indicated by the wound-healing assay

line MDA-MB-231. Its antimigratory activity was evaluated by a [102]. Therefore, waixenicin A might have implications for con-

wound-healing assay at six different concentrations, ranging from trolling the metastasis of cancer cells.

0.3125 mM to 10 mM. The reported percentage of migration of cells

at the nanomolar dose level (0.3125 mM) was approximately 52%. Obstacles associated with MNPs drug discovery

For anti-invasive activities, subereamolline A was tested at a con- Without a doubt, marine-derived entities are becoming a highlight

1

centration of 2 mM in the Cultrex BME cell invasion assay, and of modern drug discovery. This is best represented by the

eight commercially available approved drugs derived from MNPs

(Table 1). Furthermore, various marine-derived leads are currently

H3CO Br

at different stages of development in clinical trials (Fig. 1). How-

ever, there are challenges and limitations, which are listed below,

Br O

H that may hinder the discovery and development of drugs derived

HO O

O N N from the marine environment. N H

O

Availability of MNP for drug development

Drug Discovery Today

The limited sustainable supply of most bioactive natural products

FIGURE 23 is often the main obstacle hindering their further exploitation

Chemical structure of subereamolline A isolated from Suberea mollis. as drug leads [64]. During the early screening phase, sufficient

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Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS

H2N

O O H N N O

HN NH O OH O H O NH N H O OH HO HN O N N O H NH H O O O N N H HN N O N OH H O H O O FOUNDATION REVIEW NH Reviews Drug Discovery Today

FIGURE 24

Chemical structure of sungsanpin isolated from Streptomyces species.

quantities of isolated natural product are required to evaluate the to be complicated and often require multiple purification steps.

real potential, selectivity, and mechanism of the isolated sub- Even though the bioactivity-guided isolation and dereplication of

stance. After the isolation of the active natural product, its chemi- natural products have provided some success in the isolation and

cal structure determination and identification of interesting identification of novel hits, it sometimes becomes challenging to

biological activity(ies) require, at most, approximately 50 mg of identify the ‘hit’ compound from the crude extract [105]. Once the

the pure compound [103,104]. Total chemical synthesis and semi- potential of an isolated natural product is established, the next

synthesis are viable options to secure further gram-scales of mate- most-important obstacle is to secure enough quantity to meet the

rial if necessary. However, aquaculture and biotechnological market demand, which could reach hundreds of thousands of

approaches are still in the early stages of development. kilograms per year [106]. The best possible solution to the current

productivity crisis for natural product drug discovery is to adopt

Accessibility of the marine source multidisciplinary approaches [107]. Total and combinatorial syn-

Assessing deep-sea habitats for harvesting bioactive compounds is thetic methodologies, including the alteration of biosynthetic

a relatively new area in natural product drug discovery. Deep-sea pathways, can in some cases offer solutions to the supply problem

habitats have a high potential to harbor chemically and phyloge- [107,108]. However, synthetic or semisynthetic approaches still

netically novel microbes [99]. An organism has to be present at the have a significant role in the development of natural product-like

depth of more than 50 m to qualify as an inhabitant of the deep sea libraries [107]. Interestingly, in some instances, the total or

[99]. It is highly challenging to reach this depth for sample diverted synthesis of natural products has resulted in the develop-

collection. One successful example of a bioactive compound from ment of entirely new synthetic routes [109]. Both total and semi-

deep-sea animals is sungsanpin, which is the 15-amino acid lasso synthetic approaches afford the generation of natural product

peptide discussed above. Its sample was collected at a depth of – analogs or derivatives in sufficient yields.

138 m.

Identification of the pharmacological target

Availability of the infrastructure and multidisciplinary personnel It is often difficult to identify a specific molecular target for

Natural product research requires a massive investment in labora- bioactive natural products. It can take decades to discover and

tory equipment and set-up costs to conduct basic experiments. validate the macromolecular target of a specific compound. Some

Moreover, the isolation and purification of natural products tend natural product-derived scaffolds can show peculiar molecular

mechanisms (e.g., trabectedin, a commercially available drug),

while others can have multiple targets (e.g., bryostatin 1, in

O

clinical trials); therefore, they could have the potential to treat

O O

H multiple disease states [110]. O

H Concluding remarks

O O

Marine organisms survive in stressful environments and are ex-

O posed to numerous unique environmental conditions, unlike

terrestrial or freshwater-dwelling organisms. Therefore, they pro-

Drug Discovery Today

vide a variety of secondary metabolites with unusual and diverse

FIGURE 25 chemistry and interesting biological activities, which commonly

Chemical structure of waixenicin A isolated from Anthelia edmondsoni. include anticancer properties. Most traditional ancient medicines,

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REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016

TABLE 2

Marine-derived compounds with the potential to target cancer migratory and invasive cascades.

Compound name Source Total synthesis Compound identifier

BU-4664L Micromonospora sp. – PubChem: 9868980

Dieckol Ecklonia cava – PubChem: 3008868

Reviews

Frondoside A Cucumaria frondosa – PubChem: 44448161

Fucoidan Brown algae – CAS: 9072-19-9

ONAINREVIEW FOUNDATION

Geodiamolide H Geodia corticostylifera – ChemSpider: 4977358

Heteronemin Heteronema erecta – CAS: 62008-04-2

Latrunculin A; Latrunculin B Negombata magnifica Yes PubChem: 445420; 6436219

Motuporamine C Xestospongia exigua Yes PubChem: 9818652

Pachycladins A; Pachycladins D Cladiella pachyclados –; yes PubChem: 46832819; 46833117

Penicillivinacine; Terretrione A Penicillium vinaceum – None; CAS: 1558009-89-4

Penitrem A; Penitrem B; Penitrem D Penicillium commune –;–; yes PubChem: 44450809; 3084087; 76308902

Phenylmethylene hydantoin Hemimycale arabica Yes CAS: 1134426-24-6

Phidianidine A Phidiana militaris Yes PubChem: 59053149

Sarcophine Sarcophyton glaucum Yes PubChem: 6436805

Sceptrin Agelas sceptrum Yes PubChem: 157394

Sinulariolide Sinularia flexibilis – PubChem: 6440916

Sinulodurin A; Sinulodurin B Sinularia dura – PubChem: 25016150; 25016151

Sipholenol A; Sipholenol E; Sipholenone A Callyspongia siphonella – PubChem: 16757532; ChemSpider:

10470228; PubChem: 44423609

Strongylophorine-26 Petrosia (Strongylophora) corticata – PubChem: 11751458

Stylissamide X Stylissa species Yes PubChem: 57335467

Subereamolline A Suberea mollis Yes PubChem: 25016147

Sungsanpin Streptomyces species – PubChem: 71713252

Waixenicin A Anthelia edmondsoni – PubChem: 73755210

which come from various cultures, such as Chinese, Greek, Ro- and invasion of gastric cancer cells synergistically [111]. Similarly,

1

man, and Egyptian medicines as well as the Indian Ayurvedic Bosulif (bosutinib), a tyrosine kinase inhibitor, has recently

system, are based on bioactive ingredients derived from the parent shown inhibition of migration and invasion of non-small cell

natural sources. Experimental evidence of cancer-controlling and lung cancer, which could be further explored for combined

preventive properties, via inhibition of migration and invasive treatments with the MNPs listed in this review [112]. Marine-

cascades of various cancer cells, of several MNPs (Table 2) have derived natural products with their unique chemical composi-

been summarized in this review. Most of these MNPs have been tions and potential novel molecular targets could provide a

examined in vitro; therefore, further pharmacological develop- wealthy resource for the discovery of useful entities and scaffolds

ment efforts are crucial to evaluate their exact molecular mecha- for the effective and selective control of metastatic malignancy

nism(s) for the control of cancer metastasis. cascades.

Some of these MNPs might find their way into the market

1

via combined therapies with existing drugs, such as Taxol Acknowledgments

(paclitaxel). In a recent study, paclitaxel combined with harmine, The authors thank Christine Gallisdorfer for assistance with the

a natural b-carboline alkaloid, was found to inhibit the migration collection of research articles for this review.

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