Seaweeds and Their Secondary Metabolites: A Promising Drug Candidate With Novel Mechanisms Against Cancers and Tumor Angiogenesis

Abstract

Cancer continually remains a severe threat to public health and requires constant demand for novel therapeutic drug candidates. Due to their multi-target orientation, lesser toxicity, and easy availability, natural compounds attract more attention from current scientific research interest than synthetic drug molecules. The plants and microorganisms produce a huge variety of secondary metabolites because of their physiological diversification, and the seaweeds occupy a prominent position as effective drug resources. Seaweeds comprise microscopic or macroscopic photosynthetic, multicellular, eukaryotic marine algae that commonly inhabit the coastal regions. Several molecules (such as polysaccharides, lipids, proteinaceous fractions, phenolic compounds, and alkaloids) are derived from seaweeds, and those small molecules are well attractive and more effective in cancer research programs. Their structural variation, derivative diversity, and quantity vary with seaweed species and geographical origin. Their smaller molecular weight, unique derivatives, hydrophobicity, and degree of sulfation are reported to be causes of their crucial role against different cancer cells in vitro. Several reports showed that those compounds selectively discriminate between normal and cancer cells based on receptor variations, enzyme deficiency, and structural properties. The present review aimed to give a concise explanation regarding their structural diversity, extractability, and mechanism of action related to their anti-cancer activities based on recently published data.

Keywords: anticancer; cytotoxicity; epigenetics; polyphenols; seaweed; secondary metabolites.

Figure 1. Cell cycle regulation and checkpoints

The cell cycle is a highly regulated process that results in two daughter cells from a single one and consists of four stages, namely, gap stage (G1), DNA (deoxyribonucleic acid) synthesis (S), gap phase II (G2), and mitosis stage (M), respectively. Those stages are controlled and regulated by the heterodimeric coordination of cyclins (-A, -B, -C, -E) and cyclin-dependent kinases (CDK -1, -2, -4, -6, -8, -12). Many checkpoints (G1/S, G2/M, G1, and S) exist in the cell cycle to ensure smooth progression. p21 and p27 are prominent regulators in the G1 and S stages. Usually, any defect beyond the DNA repair at the S stage will induce those regulators and activate the programmed cell death pathways (apoptosis). The tumors evolved to break the normal regulators and apoptosis-influencing factors. Those checkpoints and regulators serve as drug targets for anticancer research. Image credit: Meenakshi Sundaram K.

Figure 2. Summary of cancer progression

Lifestyle modifications and other environmental factors strongly influence many metabolic imbalances, and these alterations further severely affect the equilibrium of the inflammation and oxidative stress conditions. Collectively, those complications alter the benign cells into tumor cells (cells with unregulated and disrupted cell proliferative activity). Tumors derive the ability to bypass normal cell signaling and become cancerous. Hence, it leads to the development of unconditional blood vessel formation (cancer angiogenesis) (Rb: retinoblastoma, p21, and p27: cyclin-dependent kinase inhibitors). Image credits: Meenakshi Sundaram K.

Figure 3. Seaweeds contain rich chemical diversity in view of pharmacological activities.

Image credits: Meenakshi Sundaram K.

Figure 4. Seaweed compounds exert different modes of anti-cancer mechanisms.

MMP: matrix metalloproteinases Image credits: Meenakshi Sundaram K.

Figure 5. The extraction method strongly determines the nature of bioactivity in seaweed compounds.

Seaweeds contain a variety of compounds, and the procedural variation is solely responsible for their pharmacological activities. Several studies showed that bioactive metabolites depend on the procedural variation of the extraction systems and are influenced by the geographical and seasonal parameters associated with the seaweeds. Image credits: Meenakshi Sundaram K.

Figure 6. Fucon and their derivatives are one of the major kinds of polysaccharides in seaweed. These fucons target a variety of cell cycle checkpoints and cell signaling proteins that are mostly misregulated in many types of cancers. Particularly, they induce apoptosis in cancer cells by integrating different pathways in individual cancer cells.

c-Myc: cellular myc; Clap 2: CARD-like apoptotic proteins; CARD: caspase-recruitment domains; Cyc D2: cyclin D2; MCF-7: Michigan Cancer Foundation-7; DU 145 cells: human prostate cancer cells; HTLV: human T-cell leukemia virus; TNF: tumor necrosis factor; CD: clusters of differentiation; GADD45α: growth arrest and DNA damage-inducible alpha; Hep G2: hepatocellular carcinoma; G1: gap phase; p3: tumor protein 3; p53: tumor protein 53; JNK: jun N-terminal kinase; HeLa: cervical cancer; PPAR: peroxisome-proliferator-activated receptors Image credits: Meenakshi Sundaram K.

Figure 7. Angiogenesis inhibition by seaweed extracts and their components

HIF: hypoxia-inducible transcription factors; ETC: effusion tumor cell; MMP-2: matrix metalloproteinases; APN: aminopeptidase N; C-fos: proto-oncogene c-fos; SARG: specifically androgen-regulated gene; VEGF: vascular endothelial growth factor; MAPK: mitogen-activated protein kinase; MEK: mitogen-activated extracellular signal-regulated kinase; ERK: extracellular signal-regulated kinases; p38: protein kinase 38; HUVEC: human umbilical vein endothelial cell; FGF: fibroblast growth factors; BAD: BCl2-associated agonist of cell death; BCl2: B-cell leukemia/lymphoma 2 protein Image credits: Meenakshi Sundaram K.