Understanding the function of the tumor microenvironment, and compounds from marine organisms for breast cancer therapy

Table 1 Marine compounds with potential anticancer activity against breast cancer from microorganisms and algae

Marine compound	Chemical nature	Mechanism of action	Ref.
Gallic acid (GA)	Phenolic compound	(1) Altered the expression of P53, Mcl and p21 as well as cell cycle regulators; and (2) MAP38 kinase involved in GA induced cell cycle arrest and apoptosis via downregulating cyclin Da/CDK4 and cyclin E/CDK2	Moghtaderi et al[74]
GA	Phenolic compound	(1) In combination with curcumin stimulated apoptosis by increasing the Bax expression, activating PARP and caspase 3; (2) Decreased Bcl2 expression; and (3) Arrested at sub-G1 stage
GA	Phenolic compound	Conjugated to Gold NPs, suppressed metastasis by blocking EGF dependent MMP-9 expression via suppressing stabilization of p300 and activation of NF-κB/c-Jun pathway	Chen et al[75]
Crambescidin 800	Heteropenta cyclic guanidine alkaloid	Induced cell cycle at the G2M phase by decreasing the cyclin D1, CDK-4, and -6 expression in TNBC cells via modulating Akt/NF-κB/MAPK pathway	Moon et al[102]
EPS11	Polysaccharide	(1) Inhibited lung metastasis by inhibiting cell adhesion protein CD99; and (2) Inhibited cancer cell growth by inducing anoikis via inducing Akt pathway-dependent expression of βIII-tubulin	Cao et al[77]
SWP1 and SWP2	Polysaccharide	Inhibited proliferation by inducing apoptosis, activating caspase 3/9 and disrupting the mitochondrial membrane via generation of ROS	Vaikundamoorthy et al[78]
Carrageenan	Polysaccharide	Induced apoptosis via promoting condensation of the nucleus and fragmentation of DNA as well as activating caspase 8, an extrinsic apoptotic protein	Murad et al[79]
Exopolysaccharide	Polysaccharide	(1) Inhibited the cell growth by decreasing the cyclin D1 and E expression; and (2) Induced the proliferation of B-cells and decreased production of IL-6 and TNF-1α in T-cells	Park et al[80]
Ilmycin C	Cyclic peptide	Inhibited migration and invasion by inducing apoptosis via Bax/Bcl-2 dependent caspases as well as inhibiting MMP-2 and -9 via blocking IL-6 dependent phosphorylation of STAT3	Xie et al[81]
		Inhibited growth by inducing apoptosis through activation of SR stress and reducing Bcl2 in a CHOP dependent manner	Zhou et al[82]
Molassamide	Cyclic depsipeptide	(1) Abrogated elastase-dependent migration of highly metastatic TNBC cells; and (2) Inhibited the activity of elastase and the migration of TNBC cells by targeting the expression of ICAM-1 via inhibiting the NF-κB pathway	Al-Awadhi et al[83]
Kempopeptin C	Cyclic depsipeptide	Inhibited invasion and migration by decreasing the cleavage of matriptase substrates CDCP1 and sesmoglein-2	Al-Awadhi et al[84]
Cyclic leucylproline	Cyclic peptide	Inhibited migration by inhibiting cell proliferation, inducing cell arrest via DNA damage. Mechanistically, CLP induced cell cycle arrest by blocking the expression of cyclin C, CDK4, PAK, RAC1, and p27kiP1 via targeting CD151 and EGFR signaling axis in TNBC cells	Kgk et al[85]
Galaxamide	Cyclic pentapeptide	Elicited apoptosis in BC cells by arresting at the G1 phase as well as reducing mitochondrial membrane potential via the generation of ROS	Lunagariya et al[86]
Brintonamide D	Linear peptide	Reduced the CCL27 and stimulated proliferation and progression of metastatic BC cells by targeting serine protease kallikrein 7 (KLK7). This study reported that brintonamide D targeted KLK7 by modulating CCR10, the receptor of CCL27 in BC cells	Al-Awadhi et al[87]
Iturin A	Lipopeptide	(1) Induced apoptosis by increasing sub-G1 cell population, fragmentation of DNA via inhibiting FGF-mediated phosphorylation of Akt, FoxO3a and GSK3β; (2) And reduced tumor growth by promoting translocation of FoxO3a via downregulating MAPK and Akt kinase in the xenograft model	Dey et al[88]
Halilectin-3	Sugar-binding lectin protein	Inhibited proliferation by inducing arrest at the G1 phase and apoptosis by increasing the activity of caspase 9 and autophagy by inducing the expression of light chain 3	do Nascimento-Neto et al[89]
Sinularin	Terpenoid	Reduced cell viability by halting at the G2M phase and stimulating apoptosis through activation of caspase-3 and -8 as well as PARP. In addition, it also induced DNA damage by generating ROS via stimulating oxidative stress	Huang et al[90]
Sipholenol A	Triterpene	Reduced the metastatic ability of TNBC cells by inhibiting protein tyrosine kinase 6, a key mediator of growth factor-dependent migration	Foudah et al[91]
Agelasine B	Diterpene alkaloid	(1) Induced apoptosis by inhibiting ER Ca2+ -ATPase (SERCA) activity via releasing Ca2+ from ER and inducing DNA fragmentation; (2) Reduced the Bcl2 expression and enhanced the caspase 8 expression; and (3) Induced cell death in an ER-mediated extrinsic apoptotic pathway	Pimentel et al[92]
Hirsutanol A	Sesquiterpene	(1) Reduced cell growth by inhibiting proliferation; (2) Induced apoptosis, and autophagy via generating ROS; and (3) Silenced Atg7 with siRNA and blockade of autophagy using bafilomycin A1 synergistically increased the efficacy of hirsutanol A in inducing apoptosis and inhibiting cell proliferation	Yang et al[93]
Dehydrothyrsiferol	Triterpenoid	Induced apoptosis by causing DNA fragmentation and arrest at S-phase and G2M phase	Pec et al[94]
Sodwanone	Triterpene	(1) Induced cytotoxicity to BC cells; and (2) Inhibited hypoxia-induced HIF-1α	Dai et al[95]
Pseudopterosin	Diterpene glycoside	(1) Reduced the production of IL-6, TNF-1α, and MCP-1 via blocking p65 and IkB phosphorylation; and (2) Promoted translocation of glucocorticoid receptor from nucleus to cytosol	Sperlich et al[96]
Quinazoline	Heterocyclic compound	(1) Induced apoptosis in HER+ve BC cells by reducing the Bcl2 expression and increasing the Bax expression; and (2) Promoted cell death via ROS-dependent extrinsic or intrinsic apoptotic pathways without systemic toxicity in the mouse model	De et al[97]
(3β)-Cholest-5-en-3-ol	Cholesterol	Induced cell death by activating caspase 3 and 8 as well as increasing the Bax expression and decreasing the Bcl2 expression	Sharifi et al[98]
3β,11-dihydroxy-9,11-secogorgost-5-en-9-one	Sterol	(1) Inhibited cell growth by inducing apoptosis via activation of caspase 3 and PARP and cell cycle arrest via targeting cyclin D1 and CDK6 through blocking the p38/ERK signaling pathway; and (2) Induced autophagy via generating ROS and DNA damage by increasing the expression of H2AX	Weng et al[99]
4-methyenedioxy-β-nitrostyrene	β-nitrostyrene derivatives	Inhibited migration by disrupting the focal adhesion complex as well as a network of actin stress fibers via reducing β1 integrin-dependent phosphorylation of FAK and paxillin	Chen et al[100]

CDK: Cyclin-dependent kinase; PAPR: Poly (ADP ribose) polymerase; NPs: Nanoparticles; EGF: Endothelial growth factor; MMP: Matrix metalloproteinase; NF-κβ: nuclear factor-κappa beta; TNBC: Triple-negative breast cancer; MAPK: Mitogen-activated protein kinase; ROS: Reactive oxygen species; IL: Interleukin; TNF: Tumor necrosis factor; ICAM-1: Intercellular adhesion molecule-1; CDCP1: CUB-domain containing protein 1; CLP: Cyclic dipeptide of leucine and proline; EGFR: Endothelial growth factor receptor; HIF: Hypoxia-inducible factor; MCP-1: Monocyte chemotactic protein-1; BC: Breast cancer; HER: Human epidermal growth factor receptor; FAK: Focal adhesion kinase.

Table 2 Marine compounds with potential anticancer activity against breast cancer from crustaceans

Marine compound	Chemical nature	Mechanism of action	Ref.
Hydro-alcoholic extract of crab	Chitosan and Astaxanthin	Reduced proliferation by inducing apoptosis and decreasing nitric oxide production	Moghtaderi et al[74]
Chitosan	Polysaccharide	(1) Reduced proliferation without affecting normal fibroblasts by inducing arrest at the G2M phase; and (2) Induced apoptosis by decreasing the expression of Bcl2 via elevation of p53 level	Resmi et al[104] and Mohamed et al[105]
Astaxanthin	Oligosaccharide	Induced PCD in BC cells via alteration in the cyclin D1, p53, Bax, and Bcl2 expression through inducing arrest at G0/G1 stage	Resmi et al[104] and Mohamed et al[105]
Chondroitin sulfate	Muco-polysaccharide	Inhibited angiogenesis by reducing tube formation via inhibiting the expression of VEGF	Chen et al[75]
β-carotene	Terpenoids	Stimulated apoptosis in BC cells by inducing the release of cytochrome C, increasing PPAR-γ, and p21 (WAF1/CIP1) expression and decreasing cyclooxygenase-2 expression through ROS generation	Moon et al[102]

PCD: Programmed cell death; BC: Breast cancer; VEGF: Vascular endothelial growth factor; ROS: Reactive oxygen species; PPAR-γ: Peroxisome proliferator-activated receptor gamma; WAF1/CIP1: Cyclin-dependent kinase inhibitor p21.

Table 3 Marine compounds with potential anticancer activity from marine fishes and invertebrates against breast cancer

Marine compound	Chemical nature	Mechanism of action	Ref.
n-3 PUFA, α-linolenic acid	Fatty acids	Decreased the risk of BC	Moghtaderi et al[74]
EPA, DHA, n-3 fatty acids	Fatty acids	(1) Decreased the risk of BC; and (2) Inhibited growth BC cells	Resmi et al[104] and Mohamed et al[105]
K092A and K092B	Peptides	Induced apoptosis by altering the cytoskeleton via targeting actin and tubulin and halting cell cycle at the G2M and decreasing mitochondrial activity	Resmi et al[104] and Mohamed et al[105]
Tetrahydro-isoquinoline	Alkaloid	(1) Induced death receptor-mediated apoptosis by increasing the expression of TRAIL-R1, -R2, Fas, TNF RI, and FADD; and (2) Induced mitochondrial-mediated apoptosis by decreasing the of Bcl2 and Bcl-XL expression and increasing the Bax, Bad, cytochrome C and caspase 3 expression via increasing the ROS generation	Chen et al[75]

BC: Breast cancer; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; PUFA: Polyunsaturated fatty acids; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; TNF: Tumor necrosis factor; FADD: Fas-associated protein with death domain; ROS: Reactive oxygen species.

Table 4 Marine compounds with potential anticancer activity and chemotherapeutics against breast cancer

Marine compound	Chemical nature	Mechanism of action	Ref.
Elisidepsin	Cyclic peptide	With combination of cisplatin or paclitaxel showed synergistic toxicity on BC cells by reducing the phosphorylation of Akt and inhibiting the MAPK pathway via targeting ErbB expression	Moghtaderi et al[74]
Sipholenol A	Triterpene	Increased the sensitivity of paclitaxel in BC cells by inhibiting P-gp and MRP1	Resmi et al[104] and Mohamed et al[105]
Permethyl ningalin B	Pyrrole-containingcompound	Sensitized BC cells to paclitaxel by inhibiting drug efflux activity of P-gp and increasing drug accumulation	Resmi et al[104] and Mohamed et al[105]
Trabectedin	Alkaloid	Combination with cisplatin or paclitaxel or doxorubicin showed an additive effect in the preclinical system	Chen et al[75]
Marine polysaccharide	Polysaccharide	In combination with cisplatin, synergistically inhibited the proliferation and migration by blocking the MMP-2 and MMP-9 expression	Chen et al[75]
Iturin A	Cyclo-lipopeptide	In combination with docetaxel, substantially sensitized docetaxel-resistant TNBC cells by reducing proliferation via massive arresting at the G1 stage and activating caspase 3 as well as inhibiting Akt and its downstream signaling pathways	Dey et al[119]
Renieramycin M	Tetrahydro-isoquinoline	Sensitized MCF-7 cells synergistically to doxorubicin by promoting doxorubicin-induced DNA damage, cell cycle arrest, and apoptosis via downregulating ErbB/PI3K-Akt, integrin, and focal adhesion signaling	Tun et al[120]
Sulfated polysaccharide	-	In combination with pH-sensitive DOX releasing nanosystem inhibited growth and metastasis of BC cells in tumor-bearing mice	Zhang et al[121]
Papuamine	Pentacyclic alkaloid	Inhibited colony formation of BC cells by targeting activation of JNK	Kanno et al[122]

BC: Breast cancer; MAPK: Mitogen-activated protein kinase; P-gp: P-glycoprotein; MRP: Multidrug-resistant associated protein; MMP: Matrix metalloproteinase; TNBC: Triple-negative breast cancer; DOX: Doxorubicin; JNK: c-Jun N-terminal kinase.