Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells

Abstract

Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.

Keywords: anti-angiogenesis; anti-inflammation; apoptosis; cell cycle; garcinol.

Figure 1

Chemical structure of garcinol.

Figure 2

Schematic representation of apoptosis with garcinol treatment (↑ up regulation, ↓ down regulation). Garcinol leads to cell cycle arrest in G0, G1/S, and G2/M phase via regulating binding of CDKs and cyclin molecules (Cyclin B, D and E) respectively. Garcinol leads to apoptosis via PI3K/AKT and NF-κB signaling pathways, PARP cleavage and activation of caspases. Phosphoinositide 3-kinase (PI3K), AKT serine/threonine kinase (Akt), cyclin-dependent kinases (CDKs), poly(ADP-ribose) polymerase (PARP), nuclear factor kappa B (NF-κB), Bcl-2 associated X, apoptosis regulator (Bax), inhibitor of kappa B (IκB-α), Cytochrome c (Cyt c), Cyclin dependent kinase 1 (Cdc2), ppoptotic protease activating factor 1 (Apaf-1), truncated BH3 interacting domain death agonist (tBid), Bcl-2 associated agonist of cell death (Bad), B-cell lymphoma 2 (Bcl-2), c-Jun N-terminal kinase (JNK).

Figure 3

Garcinol mediates anti-inflammatory role in tumor cells via TNF-α, IL-1, and IL-7 which in turn modulates anti-angiogenic and anti-metastatic action in tumor cells is mediated via NF-κB, Cox-2, iNOS, PI3K/AKT, ERK1/2, and Wnt/β-catenin signaling pathways. Tumor necrosis factor-alpha (TNF- α), Interleukin-1 (IL-1), Interleukin-7 (IL-7), Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase (PI3K), AKT serine/threonine kinase (Akt), extracellular signal regulated kinases 1/2 (ERK1/2), wingless (Wnt).

Figure 4

Schematic representations of garcinol and its derivatives in response to free radicals.

Figure 5

Anti-angiogenic and anti-metastatic action of garcinol. Microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin E synthase 2 (PGE2), hypoxia inducible factor-1 alpha (HIF-1α), C-X-C chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP-9), AKT serine/threonine kinase (Akt), signal transducer and activator of transcription 3 (STAT3), twist-related protein 1 (Twist1).