GINGER - Role in cancer treatment

Ginger (Zingiber officinale) is one of the ingredients most commonly used as a spice for culinary purposes and for medicinal purposes as well. The oleoresin (oily resin) from the rhizomes (roots) of ginger contains many bioactive components, such as [6]-gingerol (1-[4′-hydroxy-3′- methoxyphenyl]-5-hydroxy-3-decanone) which is the primary pungent ingredient that is believed to apply a variety of remarkable pharmacological and physiological activities.

Ginger and their extracts exhibit anti-inflammatory, anti-oxidant, antimicrobial, and recent studies also indicate its potent chemo-preventive characteristics of ginger extracts against different types of cancer. Some clinical studies, show the ginger extracts penetrates its anti-tumour actions through important mediators involved in crucial cell processes, such as cell cycle arrest, induction of cancer cell death, misbalance of redox homeostasis, inhibition of cell proliferation, angiogenesis, migration, and dissemination of cancer cells.


Table 1: Chemo-preventive activities of ginger extracts.

Ginger Extracts

​Structures

Chemo-Preventive Activities

6-Gingerol



• Blockage of the cell cycle at G2/M phase.

• Decrease of cells in the SubG0 phase.

• Depolarization and potential subsequent deterioration of the mitochondrial membrane.

• Induction of apoptosis.

• Inhibition of angiogenesis.

• Induction of growth suppression.

• Enhancement the doxorubicin efficacy.

6-Paradol



• Reduce blood glucose

6-Shogaol



• Arrest of the cell cycle in G2/M phase.

• Decrease levels of STAT3 and NF-κB-regulated target genes including volume and tumour burden.

• Restore wild type p53 function; provoke autophagy.

• Inhibit phase I enzymes (Cyt- p450 and Cyt-b5).

• Increase phase II enzymes (GST, GR, and GSH).

• Reduce the cleavage of Notch1.

• g cyclin D1.

• Induce apoptosis.

• Downregulation of surviving.

• Decrease tumour.

Zingerone



• Inhibition of TGF-β1 induced epithelial-mesenchymal transition, migration, and invasion.


Figure 1: Ginger extracts and their properties

Cell Cycle Arrest

Cell cycle is playing an important role to maintaining cell proliferation and tissue integrity, it is controlled in defined checkpoints by specific proteins and kinases that include cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) thoroughly. Deregulation of cell cycle and the cell cycle arrest are mostly responsible for cancer onset and progression.


Cyclin D1 is a protein necessary for progression through the G1 phase of the cell cycle. During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degrade as the cell enters the S phase. Cyclin D1 is considered as a regulatory subunit of Cyclin-dependent kinases (CDK4 and CDK6).


P21 is an inhibitor of cyclic-dependent kinase and acts as two-faced regulator depending on cell type, cell localization, p53 activity, and the type and level of genotoxic stress. It can acquire either onco-suppressive or onco-promoting properties depending on whether it is in a p-53 proficient or p-53 deficient environment, respectively.


Due to DNA damage or other stressors, the tumour suppressor p53 is activated, leading to momentary expression of the cyclin-dependent kinase inhibitor p21. This can trigger momentary G1 cell cycle arrest. Few studies have shown that in the clinic, the presence of p21 has been considered an indication of wildtype p53 activity.


The PI 3-Kinase/Akt signaling pathway is involved in fundamental cellular processes including protein synthesis, proliferation and survival. PI 3-kinase is activated followed by ligand binding to a range of receptors such as integrin receptors, receptor tyrosine kinases, cytokine receptors.


Ginger derivatives interfere with the proliferation and cell cycle of cancer cells by arresting cell cycle in G0/G1 or G2/Metaphases, by significantly reducing the cyclin D1 gene expression, by upregulating p21 expression, and by inhibiting PI3K(Phosphoinositide-3-kinase)/AKT (Protein kinase B-PKB)/mTOR (Mammalian target of rapamycin) and STAT3 (Signal transducer and activator of Transcription 3).


Cellular Death

Apoptosis (Programmed cell death) has become a rapid and irreversible process for its ability to eliminate defective cells. Apoptosis can usually be executed in two ways: Mitochondria-mediated intrinsic pathway and death receptor-mediated extrinsic route. In this process are involved cysteine-aspartate proteases (caspases) and the Bcl-2 family proteins such as Bax, Bcl-2. It is said that in pathological conditions such as cancer, alterations or mutations in the p53 gene are one of the main causes of apoptosis changes.


Survivin is a smallest member of the inhibitor of apoptosis protein family and results in being up-regulated in different types of human cancers. The over-expression of this protein is associated with inhibition of apoptosis, resistance to chemotherapy and a highly aggressive of tumours.


Methanolic extract of Zingiber officinale rhizome (also known as ZOME) is reported to have induced morphological changes such as cell shrinkage and nuclear condensation demonstrating apoptotic properties of ZOME. Apoptosis of these cancer cell lines can be gradually raised with an increasing order of concentration of extract, which helps us to know that apoptosis in this case can occur on dose dependent manner.


Autophagy is a self-destructive process important for balancing sources of energy in the embryo development and as a response to several triggers of cellular stress such as deprivation of growth factors and nutrients, inhibition of proteasome, inhibition of receptor tyrosine kinases/Akt/mammalian target of rapamycin (mTOR) signaling, and unbalance of ROS homeostasis and is characterized by a cascade of events including degradation of cytoplasmic proteins or entire organelles. Considering the different definitions stated for autophagy and cancer, it can be said that autophagy could act as a tumour suppressor, provoking apoptosis of type II and as tumour activator, directly affecting the cell–matrix focal adhesions (FAs), required for efficient migration and invasion of cells.


Autosis is an autophagy-dependent, non-apoptotic form of cell death which is characterized by enhanced cell substrate adhesion, focal inflation of the perinuclear space, dilation and fragmentation of endoplasmic reticulum. Cytochrome C is one among the mitochondrial proteins that is release into the cytosol when the cell is activated by apoptotic stimulus.

The chemo preventive effect of ginger extracts may be expressed by its ability to regulate some types of cellular death in cancer like apoptosis, autophagy, and autosis by elevating Bax/Bcl-2 ratio, releasing cytochrome c, activating caspases-3 and -9 and downregulating the survivin protein.


ROS Balance

Reactive oxygen species (ROS) are a group of highly reactive molecules generated through a variety of sources such as mitochondria, NADPH oxidases (Nox), xanthine oxidase (XO) and uncoupled endothelial nitric oxide synthase (eNOS), lipoxygenase, cyclooxygenase, and CYP-P450s enzymes. Elevated ROS rates have been detected in almost all different types of cancers, where they promote many aspects of tumour development and progression. Tumour cells also express increased levels of antioxidant proteins to detox from ROS, indicating that a delicate balance of intracellular ROS levels is required for cancer cell function. On the same note, ginger could play an important role in maintaining redox homeostasis sometimes by decreasing the quantity of ROS-induced tumour-promoting events.


Angiogenesis

Angiogenesis is a process of formation of new blood vessels from pre-existing endothelium which depends on series of cellular activities, such as extracellular matrix degradation, proliferation and migration of endothelial cells and differentiation of endothelial cells to form tubes. This phenomenon is controlled by positive factors such as vascular endothelial growth factor (VEGF) and negative regulators including endostatin, thrombospondin, etc. Neovascularization is elementary phenomenon in a variety of physiological processes such as embryonic development and pregnancy. Angiogenesis is an important event for tumour progression and metastatic cascade; hence it is said that many types of cancer therapies are directed against the tumour-associated vasculature.


Nuclear factor κB is a pro-inflammatory transcription factor that regulate the expression of different proteins—such as cytokines interleukin-1 (IL-1), interleukin-1 (IL-2), and interferon-γ (IFNγ)—involved in multiple cell signaling pathways associated with cancer progression and inflammation. NF-κB and IL-8, plays a crucial role in tumorigenesis and it could control the expression and function of numerous genes involved in cell proliferation, sustained angiogenesis, and evasion from apoptosis. Ginger derivatives seems to be potent anti-angiogenic substances that is said to indicate possible role in preventing cancer from becoming malignant, probably by selective inhibition of new vessel formation in tumour sites.


Multidrug Resistance

Multidrug resistance (MDR) mechanisms are associated with increased expression of the P-glycoprotein (Pgp) or increased cellular metabolism of drug detoxifying proteins, such as Glutathione-S-transferase (GST), that are correlated with increased resistance to apoptosis. Multidrug resistance-associated protein 1 (MRP1), involved in the transport of many antitumor agents, is overexpressed in many chemo resistant cancer types.


The phenomenon of multidrug resistance (MDR) in cancer is said to be associated with the overexpression of the ATP-binding cassette (ABC) transporter proteins, including multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein. MRP1 is said to play an active role in protecting cells by its ability to outflow of drugs to sub-lethal levels.

P-glycoprotein is one among the drug transporters that determine the uptake and outflow of a range of drugs. This process is said to affect their plasma and tissue concentrations. P-glycoprotein functions as a transmembrane outflow pump, pumping its substrates from inside to outside the cell.


Ginger extracts decrease β-catenin in the WNT signaling pathway, which leads to inhibition of gene transcription, involved in EMT (Epithelial-mesenchymal transition) and CSCs (Cancer stem cells), and downregulate MRP1 and GST-protein expression, involved in multidrug resistance.