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Contribution of black pepper to treating cancer



Black pepper is also known as the "king of species " and is rich in an alkaloid dietary compound called piperine (1-piperoylpiperidine) which is usually found in the roots of Piper nigrum L. (Black pepper).

It belongs to the species of the family Piperaceae and is commonly used as spices in food due to its characteristic pungent smell and it provides aromatic flavor to the food.

The biting taste of the pepper serves many pharmacological properties such as anti-inflammatory, anti-parasitic and anti-cancer. It also serves antioxidant properties which makes it best to use in lowering cholesterol levels, and improving sugar levels and has enormous potential in treating cancer.


Structure of Piperine


Piperine along with its three isomers namely - isopiperine, chavicine and isochavicine is a part of the family - Alkaloids contain a group of naturally occurring organic compounds.

Piperine is one of the alkaloid compounds which consists of a heterocyclic ring structure with a nitrogen atom.



Structure of Piperine

Mechanisms of Piperine


Fig. 1: Mechanism of Piperine

Piperine has anti-mutagenic and anti-tumour properties which help in preventing cancer by performing various mechanisms such as activation of apoptosis, inhibiting angiogenesis and stimulating cell cycle arrest.


1)Activation of Apoptotic signaling cascades


Fig. 2: Apoptosis Signaling cascades


Apoptosis or programmed cell death is a genetically regulated process which leads to the death of the cell caused by the presence or absence of certain stimuli such as DNA damage.

Certain chemo-preventive agents such as Piperine can produce apoptosis which can later lead to a delay in tumour growth.

Apoptosis usually occurs through major pathways: the mitochondria-mediated intrinsic pathway (where a cell receives a signal to destroy itself from one of its genes) and the death-receptor-mediated extrinsic pathway (where the cell receives a signal to start apoptosis from the other cells of the organism).

Piperine plays an enormous role in the treatment of triple breast cancer through the mitochondrial-mediated intrinsic pathway and inhibits proliferation. Piperine causes apoptosis by activating caspase -3 and PARP which can lead to effective cancer treatment.

Piperine has shown great signs of effectiveness in various drugs such as Adriamycin (doxorubicin ), Taxol (paclitaxel) and 5-FU chemotherapy and it can increase breast cancer sensitivity to curcumin (a component of the turmeric ).



Fig. 3: Impact on Apoptosis

Piperine has shown significant results in the treatment of prostate cancer by impairing the expression of androgen receptor (AR) in cancer cells and through reduced expression of phosphorylated STAT-3 and nuclear form - KB ( NF-kB). It exhibits anti-cancer in different cancer lines by inactivating B- catenin and stops the expression of pro-tumour cells.


2)In altering Redox - Homeostasis


Reactive oxygen species (ROS) are formed from molecular oxygen and are formed by both enzymatic and non-enzymatic reactions.

The ROS is formed by a series of enzymes which includes NADPH oxidase, xanthine oxidase, cyclo-oxygenase and cytochrome P450 enzyme system. It could also be formed from the non-enzymatic activity of the electron transport chain in mitochondria.

Piperine interferes with redox changes which influence cellular physiology in a variety of ways such as by promoting apoptosis which can suppress oxidative stress and could postpone cancer development.

In Human oral squamous cells, piperine accelerates the generation of reactive oxygen species (ROS) which eventually leads to the activation of caspases and cell cycle arrest.



Fig. 4: Impact on redox homeostasis


3)Cell-cycle Arrest

The cell cycle is one of the crucial aspects involved to maintain cell proliferation and prevent the cells from DNA damage. Some of the important cell cycle regulators are cyclins, cyclin-dependent kinases (CDks) and CDK- inhibitors.

Piperine acts as one of the most effective chemo-preventive agents to regulate the cell cycle progress by arresting the cancer cells at different phases of the cell cycle through inhibition and induction of p21.

Piperine has emerged as one of the potent chemo-preventive agents in the treatment of Triple-Negative Breast Cancer (TNBC) and hormone-dependent breast cancer cells. It blocks the growth and rapid spreading of TNBC cells by downregulating G-1-associated cyclins (cyclin D3, CDK4, E2F-1) and G-2-associated cyclins (cyclin B, CDK1 and Cdc25C proteins).

Piperine activates the caspases (an enzyme involved in controlling apoptosis) that help in the piperine-induced death in TNBC cells and causes ROS- mediated DNA damage through the phosphorylation of H2X at ser139. The activation of ataxia-telangiectasia, rad3. related protein and checkpoint kinase- 1 which leads to cell cycle arrest and apoptosis.



Fig. 5: Mechanism of Cell Cycle Arrest

4)By Inhibiting Angiogenesis

Angiogenesis is considered one of the hallmarks of cancer which is essential for the progression and metastasis of the cancer cells. It is the process of formation of new blood vessels from the pre-existing ones.

Piperine inhibits proliferation, migration and tubule formation by umbilical vein endothelial cells and also suppresses collagen-induced angiogenesis. It occurs by blocking Akt phosphorylation at Ser 473 and Thr 308 residues which leads to the inhibition of phosphoinositide -3 kinase (a key regulator of angiogenesis).

Angiogenesis greatly influences the tumour microenvironment which consists of a mixture of extracellular matrix (ECM) molecules, tumour cells, endothelial cells, cancer-associated fibroblasts and immune-sensitive cells. Piperine greatly influences the tumour - microenvironment which makes it best to use in the treatment of cancer.



Fig. 6: Depicting suppression of Angiogenesis


5)Multi-drug resistance

One of the major obstacles to effective cancer therapy is the development of resistance to multiple drugs with different targets (multi-drug resistance) and it occurs due to the changes that restrict the accumulation of the drugs by limiting uptake and affecting cell membrane lipids.

The phenomenon of MDR is linked with the overexpression of ATP- binding cassettes (ABC) transporter proteins which include multidrug resistance-associated protein (MRP1) and P- glycoprotein.

MRP-1 protects the cells by its ability to outflow drugs to their sub-lethal level whereas, on the other hand, P- glycoprotein acts as a transmembrane outflow pump which pumps its substrate from the outside to the inside of the cell.

Piperine is considered to be one of the dominant inhibitors of P-gGPand MRP-1 which binds the consensus sequence and when the two analogues of piperine: Pip1 and Pip2 are co-administered with certain drugs such as vincristine, colchicine and paclitaxel it leads to the reverse drug reaction in P-GP which ultimately leads to overexpression of cervical and colon cancer.


The activity of the drug metabolizing enzyme system

Many anticancer drugs show severe results of under and overdosing which leads to a high risk of treatment failure Drug metabolizing enzymes (DMEs) are the crucial aspect responsible for drug responses in patients undergoing chemotherapy.

Through chemo-preventive effects, piperine blocks the metabolic activation of certain pre- carcinogens by the drug metabolizing enzymes (DMEs) and inhibits the action of the drug - metabolizing enzymes CYP3A4 and other DMEs such as aryl-hydrocarbon hydroxylase (AHH), uridine diphosphate glucosyl transferase (UDP-GT) and cytochrome P450.

In lung cancer cells, piperine could reduce the activity of phase -1 enzymes such as NADPH-C reductase, cyt-p450 and Cyt-b5 and leads to a significant increase in the glutathione metabolizing enzymes (GPx, GR and G6PDH) which could act as a chemo-preventive agent.



Fig. 7: Drug metabolism system

Dosage

Black pepper can be used as a salt substitute or as a nutrient enhancer. It is usually recommended to have 1-2 tablespoons of black pepper per day but leads to severe adverse effects in some patients.





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Contribution of black pepper to treating cancer



Black pepper is also known as the "king of species " and is rich in an alkaloid dietary compound called piperine (1-piperoylpiperidine) which is usually found in the roots of Piper nigrum L. (Black pepper).

It belongs to the species of the family Piperaceae and is commonly used as spices in food due to its characteristic pungent smell and it provides aromatic flavor to the food.

The biting taste of the pepper serves many pharmacological properties such as anti-inflammatory, anti-parasitic and anti-cancer. It also serves antioxidant properties which makes it best to use in lowering cholesterol levels, and improving sugar levels and has enormous potential in treating cancer.


Structure of Piperine


Piperine along with its three isomers namely - isopiperine, chavicine and isochavicine is a part of the family - Alkaloids contain a group of naturally occurring organic compounds.

Piperine is one of the alkaloid compounds which consists of a heterocyclic ring structure with a nitrogen atom.



Structure of Piperine

Mechanisms of Piperine


Fig. 1: Mechanism of Piperine

Piperine has anti-mutagenic and anti-tumour properties which help in preventing cancer by performing various mechanisms such as activation of apoptosis, inhibiting angiogenesis and stimulating cell cycle arrest.


1)Activation of Apoptotic signaling cascades


Fig. 2: Apoptosis Signaling cascades


Apoptosis or programmed cell death is a genetically regulated process which leads to the death of the cell caused by the presence or absence of certain stimuli such as DNA damage.

Certain chemo-preventive agents such as Piperine can produce apoptosis which can later lead to a delay in tumour growth.

Apoptosis usually occurs through major pathways: the mitochondria-mediated intrinsic pathway (where a cell receives a signal to destroy itself from one of its genes) and the death-receptor-mediated extrinsic pathway (where the cell receives a signal to start apoptosis from the other cells of the organism).

Piperine plays an enormous role in the treatment of triple breast cancer through the mitochondrial-mediated intrinsic pathway and inhibits proliferation. Piperine causes apoptosis by activating caspase -3 and PARP which can lead to effective cancer treatment.

Piperine has shown great signs of effectiveness in various drugs such as Adriamycin (doxorubicin ), Taxol (paclitaxel) and 5-FU chemotherapy and it can increase breast cancer sensitivity to curcumin (a component of the turmeric ).



Fig. 3: Impact on Apoptosis

Piperine has shown significant results in the treatment of prostate cancer by impairing the expression of androgen receptor (AR) in cancer cells and through reduced expression of phosphorylated STAT-3 and nuclear form - KB ( NF-kB). It exhibits anti-cancer in different cancer lines by inactivating B- catenin and stops the expression of pro-tumour cells.


2)In altering Redox - Homeostasis


Reactive oxygen species (ROS) are formed from molecular oxygen and are formed by both enzymatic and non-enzymatic reactions.

The ROS is formed by a series of enzymes which includes NADPH oxidase, xanthine oxidase, cyclo-oxygenase and cytochrome P450 enzyme system. It could also be formed from the non-enzymatic activity of the electron transport chain in mitochondria.

Piperine interferes with redox changes which influence cellular physiology in a variety of ways such as by promoting apoptosis which can suppress oxidative stress and could postpone cancer development.

In Human oral squamous cells, piperine accelerates the generation of reactive oxygen species (ROS) which eventually leads to the activation of caspases and cell cycle arrest.



Fig. 4: Impact on redox homeostasis


3)Cell-cycle Arrest

The cell cycle is one of the crucial aspects involved to maintain cell proliferation and prevent the cells from DNA damage. Some of the important cell cycle regulators are cyclins, cyclin-dependent kinases (CDks) and CDK- inhibitors.

Piperine acts as one of the most effective chemo-preventive agents to regulate the cell cycle progress by arresting the cancer cells at different phases of the cell cycle through inhibition and induction of p21.

Piperine has emerged as one of the potent chemo-preventive agents in the treatment of Triple-Negative Breast Cancer (TNBC) and hormone-dependent breast cancer cells. It blocks the growth and rapid spreading of TNBC cells by downregulating G-1-associated cyclins (cyclin D3, CDK4, E2F-1) and G-2-associated cyclins (cyclin B, CDK1 and Cdc25C proteins).

Piperine activates the caspases (an enzyme involved in controlling apoptosis) that help in the piperine-induced death in TNBC cells and causes ROS- mediated DNA damage through the phosphorylation of H2X at ser139. The activation of ataxia-telangiectasia, rad3. related protein and checkpoint kinase- 1 which leads to cell cycle arrest and apoptosis.



Fig. 5: Mechanism of Cell Cycle Arrest

4)By Inhibiting Angiogenesis

Angiogenesis is considered one of the hallmarks of cancer which is essential for the progression and metastasis of the cancer cells. It is the process of formation of new blood vessels from the pre-existing ones.

Piperine inhibits proliferation, migration and tubule formation by umbilical vein endothelial cells and also suppresses collagen-induced angiogenesis. It occurs by blocking Akt phosphorylation at Ser 473 and Thr 308 residues which leads to the inhibition of phosphoinositide -3 kinase (a key regulator of angiogenesis).

Angiogenesis greatly influences the tumour microenvironment which consists of a mixture of extracellular matrix (ECM) molecules, tumour cells, endothelial cells, cancer-associated fibroblasts and immune-sensitive cells. Piperine greatly influences the tumour - microenvironment which makes it best to use in the treatment of cancer.



Fig. 6: Depicting suppression of Angiogenesis


5)Multi-drug resistance

One of the major obstacles to effective cancer therapy is the development of resistance to multiple drugs with different targets (multi-drug resistance) and it occurs due to the changes that restrict the accumulation of the drugs by limiting uptake and affecting cell membrane lipids.

The phenomenon of MDR is linked with the overexpression of ATP- binding cassettes (ABC) transporter proteins which include multidrug resistance-associated protein (MRP1) and P- glycoprotein.

MRP-1 protects the cells by its ability to outflow drugs to their sub-lethal level whereas, on the other hand, P- glycoprotein acts as a transmembrane outflow pump which pumps its substrate from the outside to the inside of the cell.

Piperine is considered to be one of the dominant inhibitors of P-gGPand MRP-1 which binds the consensus sequence and when the two analogues of piperine: Pip1 and Pip2 are co-administered with certain drugs such as vincristine, colchicine and paclitaxel it leads to the reverse drug reaction in P-GP which ultimately leads to overexpression of cervical and colon cancer.


The activity of the drug metabolizing enzyme system

Many anticancer drugs show severe results of under and overdosing which leads to a high risk of treatment failure Drug metabolizing enzymes (DMEs) are the crucial aspect responsible for drug responses in patients undergoing chemotherapy.

Through chemo-preventive effects, piperine blocks the metabolic activation of certain pre- carcinogens by the drug metabolizing enzymes (DMEs) and inhibits the action of the drug - metabolizing enzymes CYP3A4 and other DMEs such as aryl-hydrocarbon hydroxylase (AHH), uridine diphosphate glucosyl transferase (UDP-GT) and cytochrome P450.

In lung cancer cells, piperine could reduce the activity of phase -1 enzymes such as NADPH-C reductase, cyt-p450 and Cyt-b5 and leads to a significant increase in the glutathione metabolizing enzymes (GPx, GR and G6PDH) which could act as a chemo-preventive agent.



Fig. 7: Drug metabolism system

Dosage

Black pepper can be used as a salt substitute or as a nutrient enhancer. It is usually recommended to have 1-2 tablespoons of black pepper per day but leads to severe adverse effects in some patients.





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