Embelin: A multifaceted anticancer agent with translational potential in targeting tumor progression and metastasis

Abstract

Embelin, a natural para-benzoquinone product, is derived from plants of the Embelia genus, particularly Embelia ribes Burm.f. A staple in traditional medicinal formulations for centuries, Embelin's pharmacological actions are attributed to the hydroxyl benzoquinone present in its structure. Its therapeutic potential is bolstered by unique physical and chemical properties. Recently, Embelin, recognized as a non-peptidic, cell-permeable small inhibitor of the X-linked inhibitor of apoptosis protein (XIAP), has garnered significant attention for its anticancer activity. It demonstrates various anticancer mechanisms, such as apoptosis induction, cell cycle arrest, and autophagy, in different cancer types. Additionally, Embelin modulates several signal transduction pathways, including NF-κB, PI3Kinase/AKT, and STAT3, effectively inhibiting the proliferation of diverse cancer cell lines. This literature review illuminates the anticancer potential of Embelin, detailing its mechanisms of action and prospective clinical applications, based on relevant scientific literature from the past decade sourced from various electronic databases. See also the Graphical abstract(Fig. 1).

Keywords: Embelia ribes; Embelin; antitumor mechanisms; bioavailability; cancer; toxicity of Embelin.

Table 1. In vitro studies of Embelin against cancer

Table 2. In vivo studies of Embelin against cancer

Table 3. Summarizing the key mechanisms, including apoptosis induction, cell cycle arrest, autophagy, and the modulation of crucial signal transduction pathways, alongside their molecular components of Embelin

Figure 1. Graphical abstract

Figure 2. Illustrative diagram regarding the methodology adopted for the literature analysis

Figure 3. Structures of anticancer Embelin and its derivatives. Modification at carbonyl (blue), hydroxyl (red) and long-chain alkyl (pink)

Figure 4. Embelin induces apoptosis through extrinsic and intrinsic pathways in cancer cells. The extrinsic pathway is activated by death receptor ligands (e.g.: TRAIL & FAS). As a result, caspases 8 and 10 execute the downstream pathways, causing apoptosis. The intrinsic apoptosis pathway is activated by BH3 only proteins under stress conditions. This inhibits Bcl-2 proteins, leading to the activation of Bax and Bak. As a result, cytochrome C and Smac are released from mitochondria, forming apoptosomes with APAF-1. This leads to the activation of Caspase 9 and inducing apoptosis.

Figure 5. Embelin induces cell cycle arrest at different phases. Embelin is found to decrease the protein levels of CDC25B and CDC25C, causing arrest at the G2 phase. Embelin causes cell cycle arrest at the G1 phase by activating the p53 protein. Embelin causes cell cycle arrest at the G0/G1 phase of the cell cycle by activating the transcription factors p15, p16, p18, and p19, which inhibits CDK4/6 protein levels.

Figure 6. A schematic diagram that explains the autophagic mechanism of cell death and the role of Embelin in autophagy. Several proteins are involved in autophagy, namely ATG. Different ATGs have their potent role in the distinguished steps of autophagy. The steps of autophagy include initiation, phagophore formation and expansion leading to autophagosome formation. This autophagosome fuses with lysosome, leading to degradation. Embelin induces the conversion of LC I to LC II with the help of ATG3 and ATG7 during phagophore expansion.