*Pharmacological Properties and Health Benefits of* Capsicum *Species: A Comprehensive Review DOI: http://dx.doi.org/10.5772/intechopen.104906*

most endemic among women [26]. Current chemotherapeutic drugs are enormously utilized to destroy cancer cells. Still, in addition to targeting the diseased cells, it also kills healthy blood cells, skin, stomach, hair follicles, bone marrow, etc. As a


### **Table 3.**

*Anticancer effects of capsaicin on various cancers in in vitro and in vivo models.*

consequence of the undesirable properties and side effects of synthetic drugs, natural products have become increasingly popular over the past few decades. Capsaicin, the spicy ingredient of hot chili peppers, exhibits anti-neoplastic activity in a vast number of cancers like pancreatic cancer, colon cancer, liver cancer, lung cancer, prostate cancer, breast cancer, bladder cancer, and skin cancer [28–36]. The significant anticancer capacity of capsaicin targets multiple signaling pathways and cancer-associated genes in different phases of tumor development, including initiation, promotion, progression, and metastasis [37]. **Table 3** shows that various *in vitro* and *in vivo* models have been used to demonstrate the anticancer effects of capsaicin.

### *3.1.1 Pancreatic cancer*

Pancreatic cancer, one of the most lethal malignancies, is the seventh leading cause of cancer-related fatality globally. This disorder is broken down into two forms: pancreatic adenocarcinoma (85%, with a very poor prognosis) and pancreatic neuroendocrine tumors [50]. In patients with advanced pancreatic cancer, the survival rate is less than one year. Numerous studies have explored the possibility of improving survival in pancreatic cancer with new therapies. Over the past few years, researchers have studied the effects of capsaicin on various pancreatic cancer cell lines, including BxPC-3, AsPC-1, PANC-1, SW1990, MiaPaCa-2, and L3.6pl. Based on the results of these studies, anti-proliferative activities of capsaicin are mainly attributed to the inhibition of oxidative stress and angiogenesis, cell cycle regulation, and apoptosis induction [38, 51, 52]. The first report on the involvement of endoplasmic reticulum stress (ERS) in the induction of apoptosis in PANC-1 and SW1990 cells using capsaicin was described by Lin et al. [38]. The authors demonstrated the potency of capsaicin on the mRNA expression of two key ERS markers (GRP78 and GADD153) in PANC-1 and SW1990 cells. According to real-time PCR analysis, capsaicin significantly increased the mRNA expression of GRP78 and GADD153 in a time and dosedependent manner, suggesting ERS-mediated apoptosis and cell growth inhibition.

### *3.1.2 Colon cancer*

Globally, colon cancer is one of the most prevalent forms of cancer, posing a major public health threat. In 2020, approximately 1,148,515 people were diagnosed with colon cancer, and 576,858 people died from this disease worldwide [53]. The onset of colon cancer is associated with excessive cell proliferation and dysregulation of both cell-cycle progression and apoptosis. Additionally, "neoangiogenesis" plays an essential role in the development, growth, and metastasis of colon tumors [54]. In the majority of cases, colon tumors are only diagnosed in the later stages of the disease, because they do not manifest as pain-like symptoms. Over time, several strides have been made in researching and treating colon cancer. However, its survival rate has not significantly improved. The five-year survival rate is still less than 15% due to the available therapeutic agents showing strong adverse effects and poor effectiveness [55]. Recent research reported that capsaicin has cytotoxic effects on different human colorectal cancer cell lines, including colo 205 and RKO [42, 56]. In a 2004 study, Kim et al. presented salient findings regarding the capsaicin-induced apoptotic cell death by activating peroxisome proliferator-activated receptor (PAPR ) in HT-29 human colon cancer cells [40]. In addition, the latest study has shown that capsaicin mediates cell cycle arrest and apoptosis in two different human colon cancer cells (HCT116 and LoVo) via stabilizing and activating p53 in a time-dependent manner [41].

*Pharmacological Properties and Health Benefits of* Capsicum *Species: A Comprehensive Review DOI: http://dx.doi.org/10.5772/intechopen.104906*

### *3.1.3 Liver cancer*

Hepatocellular carcinoma is the most-encountered primary liver cancer in adults. Overall, the incidence rate of liver cancer is approximately four times higher in males than in females, and its pathogenesis is usually considered as an overlap of long-lasting processes, such as hepatic cytolysis, inflammation, liver regeneration, and fibrosis [57]. In hepatocellular carcinoma cell line HepG2, capsaicin-induced apoptosis with the involvement of intracellular Ca2+, ROS, Bcl-2 family, cytochrome c protein expression, and caspase-3 activity [58]. Co-treatment with capsaicin and sorafenib potentially inhibits cell proliferation by activating caspase-9, PARP, AMPK, acetyl CoA carboxylase phosphorylation in HepG2 and Huh-7 cells [59].

### *3.1.4 Lung cancer*

Lung cancer is the leading cause of mortality in both men and women, and it causes 1.8 million deaths annually. On the medical front, the prognosis of lung cancer is poor because it cannot produce noticeable signs and symptoms in the early stages. Being exposed to cigarette smoke/smoking is considered the most important factor involved in lung cancer development. Besides, environmental pollution and epigenetic alterations can also lead to lung cancer progression. This kind of cancer is broadly classified into two types: small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC is the predominant type of lung cancer, accounting for about 85% of cases, while SCLC is responsible for 15% of lung cancer cases [60]. Capsaicin exhibited its therapeutic efficiency in lung cancer treatment by means of inhibiting Hypoxia-inducible factor (HIF)-1α accumulation by suppressing mitochondrial respiration in human lung cancer cells (H1299, H23, A549, and H2009) [61]. Furthermore, the time-dependent antitumor effects of capsaicin on lung cancer were also described in an *in vivo* and *in vitro* study on SCLC cells and nude mice. The study showed that capsaicin-induced apoptosis is mediated by transient receptor potential vanilloid subfamily member 6 (TRPV6), intracellular calcium, and calpain pathway [62]. TRPV6 is one of the most calcium selective ion channels in the TRPV family. Its main function is to regulate calcium transport, reabsorption, and homeostasis in epithelial tissues. Calpains are a family of calcium-dependent intracellular cysteine proteases that regulate multiple cellular processes.

### *3.1.5 Prostate cancer*

Prostate cancer is the most common invasive malignancy among males. The incidence rate has increased in recent years in most regions of the world, perhaps due to improved detection methods with prostate-specific antigen (PSA) testing; however, the mortality rate has remained constant since the early 1900s. Androgen and androgen receptor (AR) play a critical role in the growth and maintenance of the prostate gland and the development of prostate tumors [63]. Prostate cancer may be connected with debilitating disease-related complications in an advanced stage, including painful bone metastases and urinary tract obstruction. microRNAs (miR-NAs) are a class of small non-coding RNAs (ncRNAs) that regulate gene expression by repressing translation and have been proven to be implicated in the regulation of crucial processes, such as proliferation, differentiation, and apoptosis in various kinds of cancer [64]. Among the miRNAs, miR-449a functions as an important tumor suppressor in many types of tumors by targeting different genes. Recently, Zheng et al.

found that capsaicin inhibits the proliferation of AR-positive prostate cancer cells (C4-2 and LNCaP) by inducing the restoration of miR-449a [65]. Additional convergent pieces of evidence have shown that the capsaicin combined with brassinin and docetaxel synergistically kills human prostate cancer cells (PC-3 and LNCaP) through metabolic regulator AMP-activated kinase and apoptosis [66, 67].

### *3.1.6 Breast cancer*

Breast cancer is the second most prevalent cancer worldwide and causes a high number of deaths among women every year. In the proliferation of breast cancer cells, NF-κB—the proinflammatory transcription factor plays a key role. It regulates more than 500 different genes and governs the expression of proteins engaged in cellular signaling pathways, leading to the development of malignancies and inflammation. Capsaicin displayed the ability to affect breast cancer cell proliferation by downregulating the FBI-1-Mediated NF-κB pathway [48]. Another target that acts on the proliferation of breast cancer cells is the human epidermal growth factor receptor-2 (HER-2), a tyrosine kinase (TK) receptor belonging to the EGFR family. A recent study by Thoennissen et al. showed capsaicin causes cell-cycle arrest and apoptosis in breast cancer cells (MCF-7, T47D, BT-474, SKBR-3, and MDA-MB231) via modulating the EGFR/HER-2 pathway [68].

Cyclin-dependent kinases (CDKs), a member of the serine/threonine-protein kinase family, can coordinate critical regulatory events during the cell cycle and transcription. Alterations in at least one CDK regulator or effector have been identified in almost all types of cancer. CDK8, as a member of the CDK family, serves a crucial role in gene transcription. Apart from this, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathways also play an important role in many aspects of cell growth and survival under both physiological and pathological conditions. Dysregulation of this pathway has been observed a various transformed cells and cancer tumors. In addition, aberrant activation of the Wnt/β-catenin signaling pathway causes β-catenin accumulation in the nucleus and can induce breast cancer. However, Wu et al. demonstrated that capsaicin inhibited breast cancer cell viability, induced G2/M cell cycle arrest, reduced CDK8 expression levels, decreased the phosphorylation of PI3K and Akt, and downregulated Wnt and β catenin expression levels in MDA MB 231 cells [69].

### *3.1.7 Bladder cancer*

Bladder cancer is a common malignancy affecting the genitourinary system. It is generally subdivided into two types: nonmuscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). About 30% of total patients are MIBC and have a high mortality rate due to distant metastases. Meanwhile, 70% of patients are NMIBC, which are likely to progress MIBC. Morphologically, bladder tumors can be divided into papillary, solid, and mixed types. However, the papillary type is predominant, especially in NMIBC [70]. A poor prognosis and resistance to chemotherapy are the two most important characteristics of this disease. Recently, Yang et al. reported capsaicin-induced cell death in human bladder cancer T24 cells through calcium entry-dependent ROS production and mitochondrial depolarization [71]. Likewise, Chen et al. also demonstrated capsaicin-induced cell cycle arrest by inhibiting cyclin-dependent-kinase in 5637 bladder carcinoma cells [72].

*Pharmacological Properties and Health Benefits of* Capsicum *Species: A Comprehensive Review DOI: http://dx.doi.org/10.5772/intechopen.104906*
