Chile Pepper - Role in Cancer Treatment

Chile paper is one of the ingredient which can be considered as a potential agent helping in treatment of the cancer by acting upon several pathways and genes which are known to be linked to several types of cancer.. Though there are improvements in modern medicine and technologies involved in cancer therapy (radiation, chemotherapy etc.), the results of the same are not a 100%. There is always a fear of recurrence and with that comes fear of losing a loved one. Owing to many reasons patients and their family tend to move towards additional methods outside the regular allopathic medicine, such as Ayurveda which involve natural herbs and ingredients mostly found in the Indian kitchen hold. Today let’s focus on Chile Pepper (Capsicum annum).

Chile pepper known for its spicy taste and pungency is used in both culinary and medicinal fields. Ayurveda classifies Chile pepper as follows:

Table 1 Characteristics of Chile Pepper

​Properties (Guna)	Dry(Ruksha), Light (Laghu), Sharp(Tikshna)
Taste (Rasa)	Pungent (Katu)
Potency (Virya)	​Hot (Ushna)

Capsicum annum comes in different varieties and shapes such as Bell pepper, Mexico chile etc. There are different capsaicinoids present as components in chile pepper. One of the most common one being Capsaicin. Capsaicin along with other capsinoids are produced as secondary metabolites and the former is responsible for the pungency. Capsaicin along with the next common capsaicinoid – hydrocapsaicin provide twice the hotness to the taste. Hotness is measured by Scoville units (represents how many times a component needs to be diluted so as to not perceive any pungency). Hence, capsaicin has 16*106 Scoville units whereas hydrocapsaicin has 15*106 Scoville units.

Fig. 1 Different properties of Chile Pepper

Apart from the above-mentioned properties, Chile pepper also has some protective effect on erythrocyte integrity, anti-lithogenic effect, pain relief and weight loss.

Capsaicin has had some positive effects on altering cancerous cell growth, angiogenesis, metastasis along with survival of these cells by attacking the expression of some essential genes, altering signaling pathways, targeting tumor suppressor gene and oncogenes in various types of cancers.

Fig.2 Structural elucidation of capsaicin

Capsaicin and Apoptosis:

Apoptosis is a cellular process which prevents unnecessary cell divisions and keeps a check on which cells need to be divided and which ones need to be discarded out of the body. It is a multistep process which involves lysosomes to excrete out an enzyme – lysozyme that digests the cells. This pathway is affected in cancerous cells. This leads to uncontrollable cell division and angiogenesis occurs to sustain these cells by providing them nourishment. Capsaicin activates this pathway(angiogenesis) in cancerous cells which ultimately leads to death of these cells. This property of capsaicin to induce apoptosis is observed in pancreatic, skin, colonic, prostatic, liver, lung, endothelial, esophageal, bladder as well as leukemic cell lines.

There are majorly two mitochondrial signaling systems namely intrinsic and extrinsic mitochondrial death pathway. Both of these pathways activate the executioner or effector caspases which eventually leads to death of the cell. These pathways along with the involved proteins are the targets for the novel therapeutic treatments.

Capsaicin acts as a noxious-stimuli to receptors such as TRPVs which damages the mitochondrial membrane as well as interferes with the release of cytochrome c which are mediated by calcium ions. TRPVs, transient receptor potential vanilloids are involved in mediation of pro-apoptotic activities through TRPV1 and TRPV6 in many different cancer cells.

DNA damage along with many stress signals activates a very common tumor suppressor gene– p53 which leads a cell towards its death. Regulation of the cell’s protein activity is very essential. Depending on phosphorylation or de-phosphorylation of amino acids, the function of that particular protein can either be fatal or advantageous to the cell. In case of apoptosis phosphorylation of serine residues direct the cells towards cell death. Same is the case with acetylation of proteins. With respect to apoptosis acetylation of sirtuin1 occurs. These are a family of signaling proteins involved in metabolic regulation. Capsaicin induces phosphorylation of serine residues and also enhances the acetylation of sirtuin1 via downregulation.

Beta catenin signaling pathway is responsible for cell proliferation, differentiation and also facilitates renewal of cancer stem cells. Capsaicin deregulates beta catenin and hence prevents the development of malignancies.

Capsaicin and Cell Cycle, Angiogenesis, Metastasis:

A cell divides and proliferates via a process called cell cycle. The process is divided into the following phases: G0/G1, S, G2/M. Each of this phase checks for proper DNA repair and replication and only those cells fulfilling all the criteria for an ideal cell can cross the check points and is then sent for further division of the cells. If even one of these phases or checkpoints is altered, there is a high chance of cancerous growth. As even cells with unrepaired DNA could be sent for cell division. There are some essential components of this cell cycle machinery and they are as follows: Cyclins, CDKs (Cyclin dependent kinases) and also CDK inhibitors. CDKs are the ones which allows the cells to pass each phase. Hence CDKs along with cyclins are very active in cancerous cells. Experiments where different cells (such as: human esophageal carcinoma cells, breast cell lines, and many such cells and cell lines) have been treated with capsaicin has shown to target these cell cycle regulators hence putting a stop to the growth of cancerous cells.

Angiogenesis is a complex process that involves formation of new blood vessels to support the cancerous cells. It is not just found in cancer cells but also in normal wound healing and embryonic development. This is a prerequisite for cancer cells without which the cancerous growth is not sustained. Metastasis is when the cancerous cells migrate from one organ to another via invading their respective vasculature. Capsaicin has shown to interfere with the angiogenic signaling pathways hence helping in preventing angiogenesis and also malignant growth.

Capsaicin and Human Osteosarcoma Cell lines:

Osteosarcoma is one of the most common aggressive long bone cancer is children and adolescents. MG 63, one of the human osteosarcoma cell lines was used to check for the effects of capsaicin by treating the cell lines with different concentrations of capsaicin for different time period. Research done on MG 63 cell lines demonstrated that capsaicin has a dose-time-dependent effect where the viability of the MG 63 cell lines was observed to be reduced. The reduction was due to apoptosis which was mediated by caspase cascade and also anti-oxidant enzyme system.

Different assays namely: TUNNEL Assay, Western Blotting and Flow Cytometric analysis were used to demonstrate the anticancer properties of capsaicin which resulted in decreased viability, apoptosis and also morphological changes in MG 53 cells.

Cell death occurs due to multiple reasons. To detect whether capsaicin induced cell death via attacking the apoptosis process, TUNNEL assay was incorporated. This assay basically detects fragmentation of DNA. TUNNEL positive cells appear green; since more number of green cells were observed, it was interpreted that cell death was due to apoptosis. Another indication for apoptosis induced cell death was the increased proportion of cells in the G0-G1 phase (as apoptosis occurs due to cell being arrested in G0/G1 phase).

There many different signaling pathways involved in apoptosis, but the three major ones are the MAPKs (Mitogen activated protein kinases), general caspase cascade and the anti-oxidant enzyme system. Observations from the conducted experiment showed that capsaicin induced apoptosis only involved two of the above signaling pathways namely, general caspase cascade and anti-oxidant enzyme system. This was interpreted due to the effects observed in the general caspase cascade inhibitor – Z-VAD-FMK and also as the decrease in the viability of the MG 63 respectively. Reactive oxygen species (ROS) usually disrupts the cells integrity by damaging the cell membrane this is nothing but damaging the cellular structures. Studies also show the involvement of ROS in capsaicin- induced apoptosis.

TRPV channels once activated via heat and some chemical mediators such as pH, increases the release of intracellular calcium ion influx which leads to cell death. Recent research materials suggest that capsaicin targets these channels so as to stimulate excessive release of the calcium ions. This eventually suppresses tumorigenesis and also leads to apoptosis of the cells.

INTAKE:

As food additives (replacing normal chilly by Chile Pepper also works).

Chile Pepper - Role in Cancer Treatment

Chile paper is one of the ingredient which can be considered as a potential agent helping in treatment of the cancer by acting upon several pathways and genes which are known to be linked to several types of cancer.. Though there are improvements in modern medicine and technologies involved in cancer therapy (radiation, chemotherapy etc.), the results of the same are not a 100%. There is always a fear of recurrence and with that comes fear of losing a loved one. Owing to many reasons patients and their family tend to move towards additional methods outside the regular allopathic medicine, such as Ayurveda which involve natural herbs and ingredients mostly found in the Indian kitchen hold. Today let’s focus on Chile Pepper (Capsicum annum).

Chile pepper known for its spicy taste and pungency is used in both culinary and medicinal fields. Ayurveda classifies Chile pepper as follows:

Table 1 Characteristics of Chile Pepper

​Properties (Guna)	Dry(Ruksha), Light (Laghu), Sharp(Tikshna)
Taste (Rasa)	Pungent (Katu)
Potency (Virya)	​Hot (Ushna)

Capsicum annum comes in different varieties and shapes such as Bell pepper, Mexico chile etc. There are different capsaicinoids present as components in chile pepper. One of the most common one being Capsaicin. Capsaicin along with other capsinoids are produced as secondary metabolites and the former is responsible for the pungency. Capsaicin along with the next common capsaicinoid – hydrocapsaicin provide twice the hotness to the taste. Hotness is measured by Scoville units (represents how many times a component needs to be diluted so as to not perceive any pungency). Hence, capsaicin has 16*106 Scoville units whereas hydrocapsaicin has 15*106 Scoville units.

Fig. 1 Different properties of Chile Pepper

Apart from the above-mentioned properties, Chile pepper also has some protective effect on erythrocyte integrity, anti-lithogenic effect, pain relief and weight loss.

Capsaicin has had some positive effects on altering cancerous cell growth, angiogenesis, metastasis along with survival of these cells by attacking the expression of some essential genes, altering signaling pathways, targeting tumor suppressor gene and oncogenes in various types of cancers.

Fig.2 Structural elucidation of capsaicin

Capsaicin and Apoptosis:

Apoptosis is a cellular process which prevents unnecessary cell divisions and keeps a check on which cells need to be divided and which ones need to be discarded out of the body. It is a multistep process which involves lysosomes to excrete out an enzyme – lysozyme that digests the cells. This pathway is affected in cancerous cells. This leads to uncontrollable cell division and angiogenesis occurs to sustain these cells by providing them nourishment. Capsaicin activates this pathway(angiogenesis) in cancerous cells which ultimately leads to death of these cells. This property of capsaicin to induce apoptosis is observed in pancreatic, skin, colonic, prostatic, liver, lung, endothelial, esophageal, bladder as well as leukemic cell lines.

There are majorly two mitochondrial signaling systems namely intrinsic and extrinsic mitochondrial death pathway. Both of these pathways activate the executioner or effector caspases which eventually leads to death of the cell. These pathways along with the involved proteins are the targets for the novel therapeutic treatments.

Capsaicin acts as a noxious-stimuli to receptors such as TRPVs which damages the mitochondrial membrane as well as interferes with the release of cytochrome c which are mediated by calcium ions. TRPVs, transient receptor potential vanilloids are involved in mediation of pro-apoptotic activities through TRPV1 and TRPV6 in many different cancer cells.

DNA damage along with many stress signals activates a very common tumor suppressor gene– p53 which leads a cell towards its death. Regulation of the cell’s protein activity is very essential. Depending on phosphorylation or de-phosphorylation of amino acids, the function of that particular protein can either be fatal or advantageous to the cell. In case of apoptosis phosphorylation of serine residues direct the cells towards cell death. Same is the case with acetylation of proteins. With respect to apoptosis acetylation of sirtuin1 occurs. These are a family of signaling proteins involved in metabolic regulation. Capsaicin induces phosphorylation of serine residues and also enhances the acetylation of sirtuin1 via downregulation.

Beta catenin signaling pathway is responsible for cell proliferation, differentiation and also facilitates renewal of cancer stem cells. Capsaicin deregulates beta catenin and hence prevents the development of malignancies.

Capsaicin and Cell Cycle, Angiogenesis, Metastasis:

A cell divides and proliferates via a process called cell cycle. The process is divided into the following phases: G0/G1, S, G2/M. Each of this phase checks for proper DNA repair and replication and only those cells fulfilling all the criteria for an ideal cell can cross the check points and is then sent for further division of the cells. If even one of these phases or checkpoints is altered, there is a high chance of cancerous growth. As even cells with unrepaired DNA could be sent for cell division. There are some essential components of this cell cycle machinery and they are as follows: Cyclins, CDKs (Cyclin dependent kinases) and also CDK inhibitors. CDKs are the ones which allows the cells to pass each phase. Hence CDKs along with cyclins are very active in cancerous cells. Experiments where different cells (such as: human esophageal carcinoma cells, breast cell lines, and many such cells and cell lines) have been treated with capsaicin has shown to target these cell cycle regulators hence putting a stop to the growth of cancerous cells.

Angiogenesis is a complex process that involves formation of new blood vessels to support the cancerous cells. It is not just found in cancer cells but also in normal wound healing and embryonic development. This is a prerequisite for cancer cells without which the cancerous growth is not sustained. Metastasis is when the cancerous cells migrate from one organ to another via invading their respective vasculature. Capsaicin has shown to interfere with the angiogenic signaling pathways hence helping in preventing angiogenesis and also malignant growth.

Capsaicin and Human Osteosarcoma Cell lines:

Osteosarcoma is one of the most common aggressive long bone cancer is children and adolescents. MG 63, one of the human osteosarcoma cell lines was used to check for the effects of capsaicin by treating the cell lines with different concentrations of capsaicin for different time period. Research done on MG 63 cell lines demonstrated that capsaicin has a dose-time-dependent effect where the viability of the MG 63 cell lines was observed to be reduced. The reduction was due to apoptosis which was mediated by caspase cascade and also anti-oxidant enzyme system.

Different assays namely: TUNNEL Assay, Western Blotting and Flow Cytometric analysis were used to demonstrate the anticancer properties of capsaicin which resulted in decreased viability, apoptosis and also morphological changes in MG 53 cells.

Cell death occurs due to multiple reasons. To detect whether capsaicin induced cell death via attacking the apoptosis process, TUNNEL assay was incorporated. This assay basically detects fragmentation of DNA. TUNNEL positive cells appear green; since more number of green cells were observed, it was interpreted that cell death was due to apoptosis. Another indication for apoptosis induced cell death was the increased proportion of cells in the G0-G1 phase (as apoptosis occurs due to cell being arrested in G0/G1 phase).

There many different signaling pathways involved in apoptosis, but the three major ones are the MAPKs (Mitogen activated protein kinases), general caspase cascade and the anti-oxidant enzyme system. Observations from the conducted experiment showed that capsaicin induced apoptosis only involved two of the above signaling pathways namely, general caspase cascade and anti-oxidant enzyme system. This was interpreted due to the effects observed in the general caspase cascade inhibitor – Z-VAD-FMK and also as the decrease in the viability of the MG 63 respectively. Reactive oxygen species (ROS) usually disrupts the cells integrity by damaging the cell membrane this is nothing but damaging the cellular structures. Studies also show the involvement of ROS in capsaicin- induced apoptosis.

TRPV channels once activated via heat and some chemical mediators such as pH, increases the release of intracellular calcium ion influx which leads to cell death. Recent research materials suggest that capsaicin targets these channels so as to stimulate excessive release of the calcium ions. This eventually suppresses tumorigenesis and also leads to apoptosis of the cells.

INTAKE:

As food additives (replacing normal chilly by Chile Pepper also works).