**2. Capsaicinoids**

The chili-fruit pungent principles are called capsaicin. Capsaicin and many related compounds are called capsaicinoids. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a crystalline, lipophilic, colorless, and odorless alkaloid that is soluble in fat, alcohol, and oil. The major capsaicinoids or the analogs from *Capsicum annum* species are Capsaicin and 6,7-dihydrocapsaicin. The smaller capsaicinoids are nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Capsaicin and their analogs differ only in acyl group saturation [4, 5]. These alkaloids are produced solely by the genus *Capsicum*, and they are used as a potent analgesic for the treatment of pain and inflammation related to a number of diseases [6, 7].

Although capsaicin traditionally is associated with the analgesic activity, its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation, limit capsaicin's applications as a clinically viable drug. This has led to extensive research focusing on the discovery and rational design of capsaicin analogs of the second generation, which have greater bioactivity than capsaicin. Modifications in the acid portion of capsaicin were found to generate analogs with different degrees of pungency. Three capsaicin analogs of two pungent and one with very low pungency were obtained by using multiple lengths of the acyl chain and chemical replacements in the aromatic ring [8]. The chemical structure of capsaicin and its analogs [9, 10] were shown in **Figure 1**.

Capsaicin (**Figure 1(1)**) and its analogs such as capsanthin (**Figure 1(2)**), capsanthin 3′-ester (**Figure 1(3)**), capsanthin 3′,3-diester (**Figure 1(4)**), capsorubin (**Figure 1(5)**), capsorubin 3′-ester (**Figure 1(6)**), and capsorubin—3,6-epoxide (**Figure 1(7)**) containing pharmaceutical products have been marketed under the trade name such as Menthacin, Zostrix, and Capzasin-P for topical applications. In 2009, the European Union (EU) and the USA Food and Drug Administration (FDA)

#### **Figure 1.**

*Capsaicin and its analogs: (1) capsaicin; (2) capsanthin; (3) capsanthin 3′-ester; (4) capsanthin 3′,3-diester; (5) capsorubin; (6) capsorubin 3′-ester; (7) capsorubin—3,6-epoxide.*

**109**

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

**3. Anticancer activity of capsaicin and its analogs**

life span, growth arrest, angiogenesis, and metastasis [15, 16].

anticancer pathways include increased cell cycle arrest and apoptosis.

**3.1 Capsaicin and apoptosis**

approved the use of capsaicin 8% patch (Qutenza or NGX-4010) for the treatment of post-herpetic neuralgia (PHN). Resiniferatoxin (RTX) is regarded as an ultrapotent analog of capsaicin that acts as an agonist of Transient receptor potential cation channel subfamily V member 1 (TRPV1) and displays several thousand-fold more potencies than capsaicin [11]. Zucapsaicin, the cis-isomer of capsaicin, shows potent efficacy against episodic cluster migraine prophylaxis, episodic cluster headache, and alleviates neuropathic pain [12]. Thus, capsaicin and its analogs have been used medicinally for centuries, but recently, it has been studied extensively for its analgesic, antioxidant, anti-inflammatory, anti-obesity characteristics and currently for its anticancer activity against a number of types of cancer [13]. It was witnessed by unparalleled advances in the field of capsaicin research. These studies and several other reports clearly showed that capsaicin and its analogs possess multiple pharmacological effects and its application in different clinical conditions.

There is a strong epidemiological and experimental evidence that the phytochemical diet found in fruits, vegetables, whole grains, spices, and teas provides various inhibitory effects against the initiation, development, progression, and metastasis of cancer [14]. Capsaicin, a bioactive phytochemical abundant in chili peppers, is in between them. Capsaicin is a derivative of homovanillic acid, which has been shown to modify the function of many genes associated with cancer cell

Tumorigenesis is a multistage process, which usually begins over an extended period. Cancer cells develop special properties not acquired by most healthy cells. Multiple genetic alterations and aberrant signaling pathways initiate and advance cancer. Determining the molecular targets involved in the tumor development process will provide opportunities to develop a successful cancer-fighting strategy. Studies assessing the capsaicin effect to inhibit cell proliferation by mechanisms are not fully understood in many types of cancer cells [17]. The capsaicin's suggested

Apoptosis is a vital mechanism against the growth of cancer, and it is strongly correlated with the loss of apoptotic signals in malignancy. It has been shown that capsaicin induces apoptosis in many different types of cancer cell lines, including pancreas, colon, prostate, liver, esophagus, bladder, skin, leukemia, lung, and endothelial cells, keeping the normal cells unharmed. A recent review noted capsaicin appears to induce apoptosis in more than 40 distinct lines of cancer cells [13, 18]. Two major signaling systems are the intrinsic mitochondrial death pathway and the extrinsic death receptor pathway, which activate executioner/effector caspases and lead to apoptosis. In specific, the mitochondrial pathway is involved in the complete execution of apoptosis; thus, the mitochondrion has been named as apoptotic mechanism's gatekeeper, and the mitochondrial death pathway proteins and pathways had become important targets for new treatments [19]. Many proteins involved in the mitochondrial death pathway have been targeted by capsaicin to induce apoptosis in different cancer cell lines. For instance, capsaicin treatment activated the cluster of differentiation 95 (CD95)-mediated apoptotic intrinsic and extrinsic pathways [20] and suppressed antiapoptotic protein expression, B-cell lymphoma 2, which causes caspase-9 and -3 activation, loss of mitochondrial membrane potential, and subsequent rises in cytochrome c release [21].

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

Capsicum

**2. Capsaicinoids**

The chili-fruit pungent principles are called capsaicin. Capsaicin and many related compounds are called capsaicinoids. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a crystalline, lipophilic, colorless, and odorless alkaloid that is soluble in fat, alcohol, and oil. The major capsaicinoids or the analogs from *Capsicum annum* species are Capsaicin and 6,7-dihydrocapsaicin. The smaller capsaicinoids are nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Capsaicin and their analogs differ only in acyl group saturation [4, 5]. These alkaloids are produced solely by the genus *Capsicum*, and they are used as a potent analgesic for the treatment of pain and inflammation related to a number of diseases [6, 7]. Although capsaicin traditionally is associated with the analgesic activity, its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation, limit capsaicin's applications as a clinically viable drug. This has led to extensive research focusing on the discovery and rational design of capsaicin analogs of the second generation, which have greater bioactivity than capsaicin. Modifications in the acid portion of capsaicin were found to generate analogs with different degrees of pungency. Three capsaicin analogs of two pungent and one with very low pungency were obtained by using multiple lengths of the acyl chain and chemical replacements in the aromatic ring [8]. The chemical structure of

Capsaicin (**Figure 1(1)**) and its analogs such as capsanthin (**Figure 1(2)**), capsanthin 3′-ester (**Figure 1(3)**), capsanthin 3′,3-diester (**Figure 1(4)**), capsorubin (**Figure 1(5)**), capsorubin 3′-ester (**Figure 1(6)**), and capsorubin—3,6-epoxide (**Figure 1(7)**) containing pharmaceutical products have been marketed under the trade name such as Menthacin, Zostrix, and Capzasin-P for topical applications. In 2009, the European Union (EU) and the USA Food and Drug Administration (FDA)

*Capsaicin and its analogs: (1) capsaicin; (2) capsanthin; (3) capsanthin 3′-ester; (4) capsanthin 3′,3-diester;* 

*(5) capsorubin; (6) capsorubin 3′-ester; (7) capsorubin—3,6-epoxide.*

capsaicin and its analogs [9, 10] were shown in **Figure 1**.

**108**

**Figure 1.**

approved the use of capsaicin 8% patch (Qutenza or NGX-4010) for the treatment of post-herpetic neuralgia (PHN). Resiniferatoxin (RTX) is regarded as an ultrapotent analog of capsaicin that acts as an agonist of Transient receptor potential cation channel subfamily V member 1 (TRPV1) and displays several thousand-fold more potencies than capsaicin [11]. Zucapsaicin, the cis-isomer of capsaicin, shows potent efficacy against episodic cluster migraine prophylaxis, episodic cluster headache, and alleviates neuropathic pain [12]. Thus, capsaicin and its analogs have been used medicinally for centuries, but recently, it has been studied extensively for its analgesic, antioxidant, anti-inflammatory, anti-obesity characteristics and currently for its anticancer activity against a number of types of cancer [13]. It was witnessed by unparalleled advances in the field of capsaicin research. These studies and several other reports clearly showed that capsaicin and its analogs possess multiple pharmacological effects and its application in different clinical conditions.
