Pro-Apoptotic Activity of Bioactive Compounds from Seaweeds: Promising Sources for Developing Novel Anticancer Drugs

Abstract

The process by which cancer cells evade or inhibit apoptosis is considered one of the characteristics of cancer. The ability of cancer cells to escape apoptosis contributes to tumor proliferation and promotes metastasis. The discovery of new antitumor agents is essential for cancer treatment due to the lack of selectivity of drugs and cellular resistance to anticancer agents. Several studies showed that macroalgae produce various metabolites with different biological activities among marine organisms. This review discusses multiple metabolites extracted from macroalgae and their pro-apoptotic effects through regulating apoptosis signaling pathway target molecules and the structure-activity relationship. Twenty-four promising bioactive compounds have been reported, where eight of these compounds exhibited values of maximum inhibitory concentration (IC50) of less than 7 μg/mL. Fucoxanthin was the only carotenoid reported that induced apoptosis in HeLa cells with an IC50 below 1 µg/mL. Se-PPC (a complex of proteins and selenylated polysaccharides) is the magistral compound because it is the only one with an IC50 of 2.5 µg/mL which regulates the primary proteins and critical genes of both apoptosis pathways. Therefore, this review will help provide the basis for further studies and the development of new anticancer drugs, both as single agents and adjuvants, decreasing the aggressiveness of first-line drugs and offering patients better survival and quality of life.

Keywords: Bcl-2 family proteins; ROS; antioxidant activity; apoptosis; bioactive compounds; cancer; caspases; extrinsic pathway; intrinsic pathway; seaweeds.

Figure 1

The extrinsic and intrinsic pathways of apoptosis. Taken and modified from D’Arcy [12]. The extrinsic pathway is triggered by external stimuli or ligand molecules, particularly involving death receptors. The intrinsic pathway is mediated by Bax/Bak pore formation into the mitochondrial membrane. Subsequently, cytochrome c is released and combines with apoptotic protease activating factor-1 (Apaf)–1 and procaspase-9 to form the apoptosome. Both pathways converge in activating executioner caspases -3, -6, and -7.

Figure 2

Different BH domains of Bcl-2 subfamilies members. Taken and modified from Jutinico et al. [18]. Bak: Bcl-2-antagonist killer 1; Bax: Bcl-2-associated X protein; Bcl: pro-apoptotic B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large Bid: BH3- interacting domain death agonist; Bmf: Bcl-2 modifying factor; Bok: Bcl-2 related ovarian killer.

Figure 3

Mechanism of induction and inhibition of pro- and anti-apoptotic proteins by p53 and induction of apoptosis. Taken and modified from Aubrey et al. [20] and Giam et al. [21]. Activation and inhibition of pro-apoptotic and anti-apoptotic proteins, respectively, through the conformational change of Bax, facilitating the permeabilization of the mitochondrial membrane by pore formation, and, consequently, the release of cytochrome c from the mitochondria to the cytosol forming the apoptosome together with cytosolic Apaf-1 and pro-caspase-9, triggering regulated death. Appreciation of the morphological and biochemical changes of apoptosis. Bad: Bcl-2 agonist of cell death; Bak: Bcl-2 antagonist killer 1; Bax: Bcl-2-associated X protein; Bcl-xL: B-cell lymphoma-extra-large; Bcl-2: B-cell lymphoma 2; Bim: Bcl-2 interacting mediator of cell death; Caspase -3, -6, -7, -9: Cysteinyl aspartic acid-protease -3, -6, -7, -9; Mcl-1: Myeloid cell leukemia-1; PUMA: p53 upregulated modulator of apoptosis.

Figure 4

Chemical structure of carotenoids. (A): β-carotene; (B): Fucoxanthin; (C): Fucoxanthinol; (D): Siphonaxanthin; (E): Siphonein.

Figure 5

Possible mechanism of action of phenolic compounds and carotenoids extracted from macroalgae inducing apoptosis. It represents the mechanism of action of some compounds such as phloroglucinol, dieckol, siphonaxanthin, fucoxanthin, and fucoxanthinol in the extrinsic and intrinsic pathway of apoptosis, modulating target molecules involved in them. Representation of the pro-oxidant action of phenolic compounds and carotenoids generates an overproduction of intracellular ROS, which causes mitochondrial dysfunction allowing the release of pro-apoptotic compounds to the cytosol, triggering apoptosis. Yellow arrows indicate positive or negative regulation of crucial proteins by these phenolic compounds and carotenoids. Apaf-1: apoptotic protease activating factor-1; ATM: Ataxia-telangiectasia-mutated; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large; Caspase -3, -6, -7, -8, -9, and 10: Cysteinyl aspartic acid-protease-3, -6, -7, -8, -9, and -10; DNA-PK: DNA-dependent protein kinase; DR 4/5: Death receptor 4/5; FADD: Fas-associated death domain; Fas: FLIP: (FADD-like IL-1β-converting enzyme)-inhibitory protein; HtrA2: High-temperature requirement protein A2; IAP: Inhibitors of Apoptosis Proteins; MOMP: Mitochondrial Outer Membrane Permeabilization; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PARP: poly (ADP-ribose) polymerase; RIP: Receptor interacting protein; SMAC/DIABLO: Second mitochondrial activator of caspases/direct IAP binding protein with low PI; TNF: Tumor necrosis factor; TNFR1: TNF receptor 1; TRADD: TNF receptor-associated death domain; TRAF2: TNFR-associated factor 2; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 6

Chemical structure of phenolic compounds extracted from macroalgae with apoptotic activity. (F): BDDPM; (G): Dieckol; (H): Phloroglucinol.

Figure 7

Chemical structure of phytosterols extracted from macroalgae. (I): Cholesterol; (J): Clerosterol; (K): Fucosterol; (L): Campesterol; (M): 22-dehydrocolesterol; (N): Desmosterol; (O): β-sitosterol; (P): Stigmasterol.

Figure 8

Possible mechanism of action of phytosterols extracted from macroalgae inducing apoptosis. It represents the mechanism of action of some compounds, such as clerosterol and fucosterol, in the extrinsic and intrinsic apoptosis pathway, modulating the target molecules involved. High mitochondrial cholesterol content has been found in different tumors resulting in partial or ineffective oligomerization of Bax that could contribute to apoptotic resistance; due to that, the capacity of phytosterols to decrease cholesterol content is crucial. Violet arrows indicate positive or negative regulation of crucial proteins by such phytosterols. Apaf-1: apoptotic protease activating factor-1; ATM: Ataxia-telangiectasia-mutated; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large; Bid: BH3- interacting domain death agonist; Caspase -3, -6, -7, -8, -9, -10: Cysteinyl aspartic acid-protease -3, -6, -7, -8, -9, -10; CAT: catalase; DNA-PK: DNA-dependent protein kinase; DR 4/5: Death receptor 4/,5; FADD: Fas-associated death domain; FLIP: (FADD-like IL-1β-converting enzyme)-inhibitory protein; HtrA2: High-temperature requirement protein A2; IAP: Inhibitors of Apoptosis Proteins; MOMP: Mitochondrial Outer Membrane Permeabilization; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PARP: poly (ADP-ribose) polymerase; RIP: Receptor interacting protein; SMAC/DIABLO: Second mitochondrial activator of caspases/direct IAP binding protein with low PI; SOD: superoxide dismutase; tBid: Truncated Bid.

Figure 9

Chemical structure of N- and O-linked glycosyl bonds of glycoproteins. (A): N-Linked and (B): O-Linked.

Figure 10

Possible mechanism of action of glycoproteins extracted from macroalgae inducing apoptosis. The mechanism of action of glycoproteins in the extrinsic and intrinsic apoptosis pathway is represented, modulating target molecules involved in them. The glycoproteins generate an overproduction of intracellular ROS, which causes mitochondrial dysfunction allowing the release of pro-apoptotic compounds to the cytosol, triggering apoptosis. Green arrows indicate positive or negative regulation of crucial proteins by these glycoproteins. Apaf-1: apoptotic protease activating factor-1; ATM: Ataxia-telangiectasia-mutated; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large; Caspase -3, -6, -7, -8, -9, -10: Cysteinyl aspartic acid-protease -3, -6, -7, -8, -9, -10; DNA-PK: DNA-dependent protein kinase; FADD: Fas-associated death domain; FLIP: (FADD-like IL-1β-converting enzyme)-inhibitory protein; HtrA2: High-temperature requirement protein A2; IAP: Inhibitors of Apoptosis Proteins; MOMP: Mitochondrial Outer Membrane Permeabilization; PARP: poly (ADP-ribose) polymerase; SMAC/DIABLO: Second mitochondrial activator of caspases/direct IAP binding protein with low PI.

Figure 11

Chemical structure of polysaccharides extracted from macroalgae with apoptotic activity. (Q): Carrageenan; (R): Fucoidan; (S): Laminarin; (T): Ulvan.

Figure 12

Possible mechanism of action of polysaccharides extracted from macroalgae inducing apoptosis. It represents the mechanism of action of some compounds such as fucoidan, laminarin, carrageenan, and ulvan in the extrinsic and intrinsic apoptosis pathway, modulating target molecules involved in them. The polysaccharides generate an overproduction of ROS and Ca²⁺ intracellular, which causes mitochondrial dysfunction allowing the release of pro-apoptotic compounds to the cytosol, triggering apoptosis. Brown arrows indicate positive or negative regulation of crucial proteins by such polysaccharides. Apaf-1: apoptotic protease activating factor-1; ATM: Ataxia-telangiectasia-mutated; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large; Bid: BH3- interacting domain death agonist; Caspase -3, -6, -7, -8, -9, -10: Cysteinyl aspartic acid-protease -3, -6, -7, -8, -9, -10; DNA-PK: DNA-dependent protein kinase; DR 4/5: Death receptor 4/5; FADD: Fas-associated death domain; Fas: FLIP: (FADD-like IL-1β-converting enzyme)-inhibitory protein; HtrA2: High-temperature requirement protein A2; IAP: Inhibitors of Apoptosis Proteins; MOMP: Mitochondrial Outer Membrane Permeabilization; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PARP: poly (ADP-ribose) polymerase; RIP: Receptor interacting protein; SMAC/DIABLO: Second mitochondrial activator of caspases/direct IAP binding protein with low PI; tBid: Truncated Bid.

Figure 13

Chemical structure of terpenes extracted from macroalgae with apoptotic activity. (U): DDSD; (V): Obtusol; (W): Elatol; (X): Mertensene; (Y): Tuberatolide B (TTB).

Figure 14

Possible mechanism of action of terpenes extracted from macroalgae inducing apoptosis. It represents the mechanism of action of some compounds such as DDSD, Tuberatolide B, elatol, obtusol, and mertensene in the extrinsic and intrinsic apoptosis pathway, modulating target molecules involved in them. DDSD and Tuberatolide B generate an overproduction of ROS intracellular, which causes mitochondrial dysfunction allowing the release of pro-apoptotic compounds to the cytosol, triggering apoptosis. Pink arrows indicate positive or negative regulation of crucial proteins by such terpenes. Apaf-1: apoptotic protease activating factor-1; ATM: Ataxia-telangiectasia-mutated; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma; Bcl-xL: B-cell lymphoma-extra-large; Bid: BH3- interacting domain death agonist; Caspase -3, -6, -7, -8, -9, -10: Cysteinyl aspartic acid-protease -3, -6, -7, -8, -9, -10; DNA-PK: DNA-dependent protein kinase; DR 4/5: Death receptor 4/5; FADD: Fas-associated death domain; FLIP: (FADD-like IL-1β-converting enzyme)-inhibitory protein; HtrA2: High-temperature requirement protein A2; IAP: Inhibitors of Apoptosis Proteins; MOMP: Mitochondrial Outer Membrane Permeabilization; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PARP: poly (ADP-ribose) polymerase; RIP: Receptor interacting protein; SMAC/DIABLO: Second mitochondrial activator of caspases/direct IAP binding protein with low PI; tBid: Truncated Bid.