**3.5 Capsaicin and β-catenin**

β-catenin is a beneficial 90 kD protein that leads to cell growth under normal physiological conditions. It is a key transcription factor in the signaling of Wingless-Int (Wnt) and plays a vital role in stem cell regeneration and organ regrowth. Abnormal expression of β-catenin causes the malignant conversion of normal cells, and its anomalous activity has been documented in several cancer types. β-catenin is essentially active in many types of cancer cells. In a recent study, it was reported that capsaicin downregulated β-catenin transcription, decreased its protein stability, and caused apoptosis of colorectal cancer cells [38].

## **3.6 Capsaicin and angiogenesis**

Angiogenesis is the development of new blood vessels from preexisting vasculature as well as an important homeostatic process for normal wound healing and embryonic growth. It involves the stimulation of endothelial cells, cell proliferation, invasion, chemotactic migration, and differentiation into new blood vessels [39]. Angiogenesis is a central player in cancer cell growth and tumor metastasis. The development of an angiogenic phenotype is regarded as a vital step in the progression of tumors [40, 41]. The cancer cells grew to 1–2 mm3 in thickness in absence of circulation and stopped, but in the angiogenic area, they expanded beyond 2 mm3 . Tumors can become necrotic or even apoptotic in the absence of vascular support [42]. Thus, angiogenesis is a significant factor in cancer progression.

Some factors such as growth factors, cytokines, and vascular endothelial growth factor (VGEF) regulate angiogenesis. Nevertheless, VEGF plays a significant role in angiogenesis. In addition, endothelial cells produce growth factors that induce autocrine and paracrine growth of tumors. The initiation of angiogenesis correlates with the increased entry into the circulation of neoplastic cells and thus promotes metastasis [43]. Treatment of endothelial cells with capsaicin blocked the sprouting and development of VEGF-induced vessels in Matrigel mouse assay that was correlated with downregulation of p38 mitogen activated protein kinases (MAPK), protein kinase B (PKB), and focal adhesion kinase (FAK) activation [44, 45].

Furthermore, capsaicin enhanced deterioration of hypoxia-inducible factor1α, which is a crucial transcription factor rising VEGF transcription. Capsaicin thus interferes with typical angiogenic signaling pathways and can have the ability to suppress cancer becoming a malignant one. It was reported that capsaicin's antiangiogenic activity was associated with reduced cyclin D1 expression, which results in decreased Rb phosphorylation, leading to the GI arrest of human endothelial cells of the umbilical cord (HUVEC) [46]. In addition, capsaicin also inhibited focal adhesion kinase (FAK) and p38 kinase activation caused by VEGF. All of the above results indicate that capsaicin is a dietary anti-angiogenic agent.

#### **3.7 Capsaicin and metastasis**

Cancer metastasis is the hallmark of tumor malignancy, which starts with the spread of cancer cells from the principal tumor to nearby tissues and distant organs, and it is the main cause of cancer morbidity and mortality. Metastatic cancer is resistant to treatment and contributes 80% of cancer-related deaths, which remains a great problem for cancer therapy [47]. Invasion and movement of tumor cells include the proteolytic degradation of extracellular matrix components by tumor cell-secreted proteases, involving serine proteases, plasminogen activators, and matrix metalloproteinases (MMPs).

**113**

*Anticancer Effect of Capsaicin and Its Analogues DOI: http://dx.doi.org/10.5772/intechopen.91897*

Human colorectal

Human prostate cancer

Human myeloid leukemia

Human esophageal epidermoid carcinoma

Human KB cancer

Human pancreatic

Human multiple myeloma

cells

cancer

Human nasopharyngeal carcinoma

Human gastric carcinoma

Human bladder cancer

cancer

**Cancer type Cell line Effective** 

T47D, BT-474, SKBR-3

> AsPC-1, BxPC-3

DU-145 500 RWPE-1 40

Human melanoma A375 100 Inhibited cell growth and promoted

Mouse melanoma B16-F10 50 Inhibited cell migration. Induced apoptosis

Human hepatoma Hep G2 10–200 Decreased cell viability, generated ROS and

**doses (μM)**

Human breast cancer MCF-7 50–300 Induced autophagy, inhibited growth, and

HCT 116 100–200 Induced autophagy

LoVo, SW480 100 Induced anti-tumorigenesis; deregulation of

Colo 205 150 Induced cell death, increased ROS, and

MDA-MB231 20–200 Induced apoptosis and dysfunctions in

LNCaP 40–50 Inhibited proliferation and induced

HL-60 >50 Induced G0/G1 phase cell cycle arrest and

U937, THP-1 200 Enhances the apoptotic effects of TRIAL by

CE 81 T/VGH 100 Induced apoptosis and G0/G1 phase cell

KB cells 150–200 Reduced cell proliferation and viability.

PANC-1 200 Induced G0/G1 phase cell cycle arrest and

Hep3B 200 Enhances the apoptotic effects of TRIAL by

T24 100 Induced ROS production and mitochondrial

NPC-TW 039 200–400 Induced G0/G1 phase arrest and apoptosis.

SMC-1 200 Induced apoptosis

U266, MM.1S >5 Inhibited cell proliferation, caused

apoptosis PC-3 20–50

**Anticancer mechanism**

β-catenin/TCF-dependent signaling

proapoptotic proteins

induced apoptosis

mitochondria. Antiproliferative activity and arrest of cell cycle into G2/M phase. Enhances the apoptotic effects of TRIAL by activating the calcium-CaMKII-Sp1 pathway

apoptosis

activating the calcium-CaMKII-Sp1 pathway

cycle arrest

apoptosis

Induced cell death and cell cycle arrest in G2/M phase

and generated ROS

apoptosis; and inhibited growth

accumulation of cells in G1 phase

activated caspase-3; and induced apoptosis and autophagy

activating the calcium-CaMKII-Sp1 pathway

Increased ROS

membrane depolarization

150 Inhibited proliferation. Induced apoptosis

200 Inhibited growth and increased apoptosis

#### *Anticancer Effect of Capsaicin and Its Analogues DOI: http://dx.doi.org/10.5772/intechopen.91897*

Capsicum

**3.5 Capsaicin and β-catenin**

**3.6 Capsaicin and angiogenesis**

(FAK) activation [44, 45].

**3.7 Capsaicin and metastasis**

matrix metalloproteinases (MMPs).

β-catenin is a beneficial 90 kD protein that leads to cell growth under normal physiological conditions. It is a key transcription factor in the signaling of Wingless-Int (Wnt) and plays a vital role in stem cell regeneration and organ regrowth. Abnormal expression of β-catenin causes the malignant conversion of normal cells, and its anomalous activity has been documented in several cancer types. β-catenin is essentially active in many types of cancer cells. In a recent study, it was reported that capsaicin downregulated β-catenin transcription, decreased its protein stabil-

Angiogenesis is the development of new blood vessels from preexisting vasculature as well as an important homeostatic process for normal wound healing and embryonic growth. It involves the stimulation of endothelial cells, cell proliferation, invasion, chemotactic migration, and differentiation into new blood vessels [39]. Angiogenesis is a central player in cancer cell growth and tumor metastasis. The development of an angiogenic phenotype is regarded as a vital step in the progres-

circulation and stopped, but in the angiogenic area, they expanded beyond 2 mm3

Tumors can become necrotic or even apoptotic in the absence of vascular support

Some factors such as growth factors, cytokines, and vascular endothelial growth factor (VGEF) regulate angiogenesis. Nevertheless, VEGF plays a significant role in angiogenesis. In addition, endothelial cells produce growth factors that induce autocrine and paracrine growth of tumors. The initiation of angiogenesis correlates with the increased entry into the circulation of neoplastic cells and thus promotes metastasis [43]. Treatment of endothelial cells with capsaicin blocked the sprouting and development of VEGF-induced vessels in Matrigel mouse assay that was correlated with downregulation of p38 mitogen activated protein kinases (MAPK), protein kinase B (PKB), and focal adhesion kinase

Furthermore, capsaicin enhanced deterioration of hypoxia-inducible factor1α, which is a crucial transcription factor rising VEGF transcription. Capsaicin thus interferes with typical angiogenic signaling pathways and can have the ability to suppress cancer becoming a malignant one. It was reported that capsaicin's antiangiogenic activity was associated with reduced cyclin D1 expression, which results in decreased Rb phosphorylation, leading to the GI arrest of human endothelial cells of the umbilical cord (HUVEC) [46]. In addition, capsaicin also inhibited focal adhesion kinase (FAK) and p38 kinase activation caused by VEGF. All of the above

Cancer metastasis is the hallmark of tumor malignancy, which starts with the spread of cancer cells from the principal tumor to nearby tissues and distant organs, and it is the main cause of cancer morbidity and mortality. Metastatic cancer is resistant to treatment and contributes 80% of cancer-related deaths, which remains a great problem for cancer therapy [47]. Invasion and movement of tumor cells include the proteolytic degradation of extracellular matrix components by tumor cell-secreted proteases, involving serine proteases, plasminogen activators, and

in thickness in absence of

.

ity, and caused apoptosis of colorectal cancer cells [38].

sion of tumors [40, 41]. The cancer cells grew to 1–2 mm3

[42]. Thus, angiogenesis is a significant factor in cancer progression.

results indicate that capsaicin is a dietary anti-angiogenic agent.

**112**



*TCF: T-cell factor; ROS: reactive oxygen species; TRIAL: TNF-related apoptosis-inducing ligand; CaMKII-Sp1: calcium-calmodulin-dependent kinase II signaling pathway I.*

#### **Table 1.**

*Anticancer potential of capsaicin against various cancer cell lines.*

Capsaicin revealed its anti-invasive and anti-migratory activity by modulating signaling pathways including cell invasion and migration and suppressing advanced cancer stages. Treatment with capsaicin significantly reduced the metastatic burden in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. It has been reported that it significantly inhibited the migration of melanoma cells without leading to apparent cellular cytotoxicity [48]. This effect was associated with the downregulation of the signaling cascade of phosphoinositide 3-kinase (PI3 K) and reduction of the RAS-related c3 botulinum toxin substrate 1 (RAC1), which in itself is the main kinase controlling motility and migration of cells. Capsaicin blocked the invasion and migration of human fibrosarcoma cells triggered by epidermal growth factor (EGF) by downregulation of AKT/FAK, extracellular signal-regulated kinases, and p38 MAPK signaling, and subsequent downregulation of matrix metallopeptidase 9 (MMP9) in invasive fibrosarcoma cells.

Thereby, capsaicin recruits several mechanisms of signaling for controlling migration and invasion. These include epithelial-mesenchymal transition (EMT) activation, AMP-activated protein kinase (AMPK), MMP signaling pathway, intracellular calcium elevation, VEGF, Wnt-Hedgehog control, tumor-associated NADH oxidase (tNOX), protein kinase B (Akt), MMPs, epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), p38 MAP kinase, RAC1, nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-kB), and AP-1 [49–54]. **Table 1** depicts the anticancer potential of capsaicin against various cancer cell lines.

#### **4. Synergistic anticancer activity of capsaicin with other compounds**

Recent development has allowed synergistic drugs to treat a wide array of cancers. Combinations of low doses of chemopreventive agents have progressively been used clinically in the treatment of various cancers in the present days. Compared to the traditional single drug policy, the combination strategy increases therapeutic effects or reduces drug resistance [55]. Computational progress in qualitatively testing and predicting synergistic components has been experienced in the last few years [56–58]. Multiple studies have illustrated that novel combination therapies with different phytochemicals and chemopreventive drugs can elicit increased antitumor activity through additive or synergistic action [59, 60].

The pathways can include parallel action on cancer suppression by modifying carcinogen detoxification and metabolism of hormones, scavenging oxidative stress, and enhancing immunity [61–63]. Hundreds of phytochemicals have various physicochemical and kinetic properties that target different signaling pathways and transcription factors that decide the phenotype of cancer. The use of several bioactive compounds with distinct anticancer pathways could, therefore, be a promising method for successful cancer treatment and prevention.

**115**

cancer [70].

**5. Conclusion**

**Conflict of interest**

*Anticancer Effect of Capsaicin and Its Analogues DOI: http://dx.doi.org/10.5772/intechopen.91897*

Capsaicin and other compounds are known to have synergistic anticancer properties. Combined with resveratrol, capsaicin facilitated apoptosis by elevating nitric oxide (NO) via a p53-dependent manner [64]. It has synergistic anticancer activity with pirarubicin, an anthracycline drug, by activating TRPV1 in bladder cancer [65]. Capsaicin shows a synergistic effect with the dietary phytoestrogen, genistein by regulation of AMPK and cyclooxygenase 2 in breast cancer cells [66]. Capsaicin and 3,3′-diindolylmethane, a key in vivo metabolite of indole-3-carbinol, abundantly present in cruciferous vegetables, have recently been reported to work synergistically to induce apoptosis in colorectal cancer, by altering the transcriptional function of the nuclear factor kappa B, p53, and control apoptosis-related genes [67]. Capsaicin, and brassinin, a form of indole derived from cruciferous vegetables, showed synergistic anticancer activity by suppressing MMP2 and -9 expression and enzymatic activities, and invasion, and migration of prostate carcinoma cells [68]. Sometimes, capsaicin also interacts with chemotherapy drugs. For example, in some myeloid leukemia cells [69], capsaicin enhanced the therapeutic efficacy with 12-O-Tetradecanoylphorbol-13-acetate. Capsaicin can, surprisingly, affect the viability of cancer stem cells. Capsaicin has been found to cause cancer stem cell death by inhibiting the NOTCH signaling pathway in stem cells of breast

An emerging cancer research area is the search for suitable molecular targets and effective anticancer compounds that modify the cancer targets. Capsaicin exhibits significant anticancer activity in various tumor stages by targeting multiple signaling pathways and cancer-associated genes. As a whole, capsaicin's anticancer pathways involve apoptosis initiation, cell growth arrest, and suppression of angiogenesis and metastasis. Capsaicin and its analogs activate the tumor-suppressive signaling pathway and associated transcription factors while inhibiting oncogenic signaling pathways and cancer cell promoters. In addition, capsaicin acts synergistically with other anticancer agents, allowing for the potential use of capsaicin with other chemotherapeutic agents in cancer therapy, and shows double advantage, i.e., capsaicinoids enhances the chemotherapeutic effect and pain relief for cancer patients. More research on capsaicin's and its analogs as anticancer targets holds the potential for future treatments and requires more study to improve our understand-

ing of its efficacy in cancer treatment and prevention.

The authors have none to declare.

*Anticancer Effect of Capsaicin and Its Analogues DOI: http://dx.doi.org/10.5772/intechopen.91897*

Capsicum

**Table 1.**

Human small cell lung cancer

Capsaicin revealed its anti-invasive and anti-migratory activity by modulating signaling pathways including cell invasion and migration and suppressing advanced cancer stages. Treatment with capsaicin significantly reduced the metastatic burden in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. It has been reported that it significantly inhibited the migration of melanoma cells without leading to apparent cellular cytotoxicity [48]. This effect was associated with the downregulation of the signaling cascade of phosphoinositide 3-kinase (PI3 K) and reduction of the RAS-related c3 botulinum toxin substrate 1 (RAC1), which in itself is the main kinase controlling motility and migration of cells. Capsaicin blocked the invasion and migration of human fibrosarcoma cells triggered by epidermal growth factor (EGF) by downregulation of AKT/FAK, extracellular signal-regulated kinases, and p38 MAPK signaling, and subsequent downregulation of matrix metal-

*TCF: T-cell factor; ROS: reactive oxygen species; TRIAL: TNF-related apoptosis-inducing ligand; CaMKII-Sp1:* 

**doses (μM)**

**Anticancer mechanism**

50 Suppressed growth in all four cell lines

Thereby, capsaicin recruits several mechanisms of signaling for controlling migration and invasion. These include epithelial-mesenchymal transition (EMT) activation, AMP-activated protein kinase (AMPK), MMP signaling pathway, intracellular calcium elevation, VEGF, Wnt-Hedgehog control, tumor-associated NADH oxidase (tNOX), protein kinase B (Akt), MMPs, epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), p38 MAP kinase, RAC1, nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-kB), and AP-1 [49–54]. **Table 1** depicts the anticancer potential of capsaicin against

**4. Synergistic anticancer activity of capsaicin with other compounds**

antitumor activity through additive or synergistic action [59, 60].

method for successful cancer treatment and prevention.

Recent development has allowed synergistic drugs to treat a wide array of cancers. Combinations of low doses of chemopreventive agents have progressively been used clinically in the treatment of various cancers in the present days. Compared to the traditional single drug policy, the combination strategy increases therapeutic effects or reduces drug resistance [55]. Computational progress in qualitatively testing and predicting synergistic components has been experienced in the last few years [56–58]. Multiple studies have illustrated that novel combination therapies with different phytochemicals and chemopreventive drugs can elicit increased

The pathways can include parallel action on cancer suppression by modifying carcinogen detoxification and metabolism of hormones, scavenging oxidative stress, and enhancing immunity [61–63]. Hundreds of phytochemicals have various physicochemical and kinetic properties that target different signaling pathways and transcription factors that decide the phenotype of cancer. The use of several bioactive compounds with distinct anticancer pathways could, therefore, be a promising

lopeptidase 9 (MMP9) in invasive fibrosarcoma cells.

**Cancer type Cell line Effective** 

*calcium-calmodulin-dependent kinase II signaling pathway I.*

*Anticancer potential of capsaicin against various cancer cell lines.*

NCI-H69, NCI-H82, DMS53, DMS114

various cancer cell lines.

**114**

Capsaicin and other compounds are known to have synergistic anticancer properties. Combined with resveratrol, capsaicin facilitated apoptosis by elevating nitric oxide (NO) via a p53-dependent manner [64]. It has synergistic anticancer activity with pirarubicin, an anthracycline drug, by activating TRPV1 in bladder cancer [65]. Capsaicin shows a synergistic effect with the dietary phytoestrogen, genistein by regulation of AMPK and cyclooxygenase 2 in breast cancer cells [66]. Capsaicin and 3,3′-diindolylmethane, a key in vivo metabolite of indole-3-carbinol, abundantly present in cruciferous vegetables, have recently been reported to work synergistically to induce apoptosis in colorectal cancer, by altering the transcriptional function of the nuclear factor kappa B, p53, and control apoptosis-related genes [67]. Capsaicin, and brassinin, a form of indole derived from cruciferous vegetables, showed synergistic anticancer activity by suppressing MMP2 and -9 expression and enzymatic activities, and invasion, and migration of prostate carcinoma cells [68]. Sometimes, capsaicin also interacts with chemotherapy drugs. For example, in some myeloid leukemia cells [69], capsaicin enhanced the therapeutic efficacy with 12-O-Tetradecanoylphorbol-13-acetate. Capsaicin can, surprisingly, affect the viability of cancer stem cells. Capsaicin has been found to cause cancer stem cell death by inhibiting the NOTCH signaling pathway in stem cells of breast cancer [70].
