The Two Faces of Capsaicin

The Conflicting Role of Capsaicin Derived from Cell and Animal Studies

The majority of the literally hundreds of basic research studies suggest that capsaicin can induce cell-cycle arrest or apoptosis or inhibit proliferation in a variety of cancer cells, suggesting that it has potent chemopreventive activities (reviewed most recently in ref. 8). Despite all the work supporting a chemopreventive role for capsaicin in cancer cell culture models, a complete consensus about whether the primary effect of capsaicin is cancer prevention or causation has not yet been reached. However, capsaicin has also been reported to be mutagenic (9) and to induce an increase in the cell viability and proliferation of the androgen-responsive prostate cancer LNCaP cells corresponding with increased androgen receptor expression (10). This discrepancy might be due, at least partially, to the inherent difficulty, such as frequent need to renew primary cultures because of dedifferentiation, in studying the effects of capsaicin in relevant “normal cell” control groups for comparison with cancer cells, which are pathologic.

Animal studies have also yielded ambiguous results. Several studies have shown a carcinogenic effect. For example, approximately 60% of rats fed a semisynthetic diet, containing 10% chilies, developed neoplastic changes in the liver (11). Swiss albino mice fed capsaicin (0.03%) in a semisynthetic diet over their lifetime developed benign polypoid adenomas of the cecum (12). Capsaicin (0.002% in drinking water for 6 weeks) was reported to act as a promoter for the development of diethylnitrosamine-initiated, enzyme-altered foci in the liver of male rats (13). Chili extract has also been shown to have a promoting effect on the development of stomach and liver tumors in BALB/c mice initiated by methyl-acetoxy methylnitrosamine and benzene hexachloride, respectively (14). In another study, rats fed diets containing hot chili pepper showed slightly higher incidence of N-methyl-N-nitrosoguanidine–induced gastric cancer (15). Furthermore, systemic denervation of sensory neurons caused by treatment with capsaicin (125 mg/kg) resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls (16). In contrast, mice fed up to a 0.25% capsaicinoid mixture (64% capsaicin and 32.6% dihydrocapsaicin) in the diet for 79 weeks showed no evidence of carcinogenicity (17).

Capsaicin effectively inhibited tumor growth and induced apoptosis in nonobese diabetic severe combined immunodeficient mice (18) and, even when administered intraperitoneally (i.p.) to adult male mice over an 8-week period, had no mutagenic effects (19). Dermal application of capsaicin did not result in an increased incidence of preneoplastic or neoplastic skin lesions in male or female Tg.AC mice (20). Application of capsaicin followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) onto shaven backs of female ICR mice resulted in no significant increases in incidence and multiplicity of skin tumors. Repeated topical applications of capsaicin alone failed to promote 7,12dimethylbenz(a)anthracene (DMBA)–initiated mouse skin tumorigenesis but moderately inhibited the papilloma formation when given prior to each topical dose of phorbol ester (21). However, capsaicin was also reported to have no effect on preventing nitrosamine 4 (methylnitrosamino)I(3-pyridyl) 1 butanone (NNK)–induced lung tumor development (22). Overall, animal studies suggest no apparent relationship between mode of administration (i.e., i.p., oral, or topical application) and susceptibility to cancer development.

The Controversial Role of Capsaicin Obtained from Human Studies

In contrast to the results of cellular and animal studies, several epidemiologic studies seem to indicate that consumption of hot peppers, which contain various levels of capsaicin, might be associated with an increased risk of cancer, and especially gallbladder (23) or gastric cancer (24). However, the argument has been made that many of the epidemiologic studies had severe limitations, such as statistical imprecision of some analyses, potential misclassification of subjects by exposure, possible recall bias, or poor control of confounding factors. Most are descriptive, correlative studies and draw speculative conclusions. Despite these limitations, the studies are cited continually in the literature as support for a cancer-promoting or causative effect of capsaicin. For example, red chili powder was found to be a risk factor for cancer of the oral cavity, pharynx, esophagus, and larynx in India (25). Significantly higher rates were observed for stomach and liver cancer in U.S. counties inhabited by Mexican-American, Cajun, white Creole, and black Creole ethnic–cultural groups who consume high levels of pepper compared with individuals who consume low amounts of hot peppers living in nearby and distant control counties matched for ethnic–cultural groups. From statistical analysis, the authors found a strong association between stomach cancer and capsaicin pepper (26). However, these authors also noted that other underlying unidentified ethnic, social, or cultural factors, for which high pepper use is a marker in the 3 different cultures, could be responsible for the observed associations. Researchers from Sungkyunkwan University (Seoul, Korea) proposed that capsaicin altered the metabolism of chemical carcinogens and might promote carcinogenesis at high doses (27). On the other hand, in an Italian case–control study, chili was briefly mentioned as being protective against stomach cancer (28). However, this finding was refuted by others (24), who indicated that chili peppers are not heavily consumed in northern Italy, where the study was conducted. In contrast, bladder biopsies from patients who were treated with capsaicin over a 5-year period were examined, and none of the bladder biopsies showed metaplasia, dysplasia, flat carcinoma in situ, papillary, or solid invasive cancer, suggesting a lack of carcinogenic activity by capsaicin (29).

Conflicting results about the effects of capsaicin on mucosal damage have also been observed. One study showed no mucosal erosions or other abnormalities after consumption of ground jalapeño peppers, even when placed directly in the stomach (30). In contrast, another study showed grossly visible gastric bleeding and mucosal microbleeding after consumption of red and black pepper (31).

Animal and cell models are potentially powerful preclinical tools in the study of the pharmacologic behavior of small molecules like capsaicin. The apparent disconnect between the animal, cellular, and human studies involving the effects of capsaicin emphasizes the recurrent difficulty in translating data obtained from cellular and animal studies to the human situation. For example, most cancer studies rely heavily on transformed cell lines or mouse models. Unfortunately, most cancer cell lines have adapted to long-term cell culture and undergone major changes in their genome. Most are likely aneuploid, which renders each cancer cell type unique in terms of gene and protein regulation and signaling and other biological behaviors. Even cell lines derived from the same tissue source can yield contradictory information, which makes the extrapolation of data from cell lines to the human patient meaningless. Transgenic and knockout mouse models are very powerful but also have substantial limitations. Overexpression or knockout of a particular gene can result in cellular adaptations that might be misleading. In addition, mouse and human tissues differ in many ways, including oncogene and oncoprotein signaling targets and susceptibility to malignant transformation. In addition, drugs and dietary factors are likely metabolized differently. Thus, the extrapolation of preclinical data to clinical reality remains challenging and capsaicin is no exception.

The Paradox of Topical Application of Capsaicin

Capsaicin is unique among naturally occurring irritant compounds because the initial neuronal excitation evoked is followed by a long-lasting refractory period, during which time the previously excited neurons are no longer responsive to a broad range of apparently unrelated stimuli (32). This process is referred to as desensitization and has been exploited for its therapeutic potential. In effect, capsaicin-containing creams have been in clinical use for many years to relieve painful conditions such as diabetic neuropathy (33). Capsaicin is the key ingredient in the experimental drug Adlea (ALRGX-4975; Anesiva, Inc.), which is in phase III trials as a long-acting analgesic to treat postsurgical and osteoarthritis pain for weeks to months after a single injection to the site of pain (34). Degeneration of epidermal nerve fibers has been suggested to contribute to the analgesic effect credited to capsaicin (35). A high-concentration (640 μg/cm²) capsaicin patch [(NG-4010) Qutenza; NeurogesX, Inc.] has been clinically evaluated for managing peripheral neuropathic pain. Systemic capsaicin exposure after single 60- or 90-minute application was determined from plasma samples, and results revealed a relatively low systemic exposure and a short half-life (∼1.6 hours) for capsaicin (36).

Topical capsaicin has been suggested as an effective pain management adjunct for rheumatoid arthritis, osteoarthritis, neuralgias, diabetic neuropathy, and other conditions including neural dysfunction, inflammation, and painful or itching cutaneous disorders resulting from surgery, injury, or tumors (33). However, even in this arena, evidence for the effectiveness or safety of capsaicin use in pain relief is controversial. Application of capsaicin to the skin causes an enhanced sensitivity to noxious stimuli, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitization (37). Capsaicin-induced dermal pain is common after exposure to capsaicin-containing hot peppers, personal protection sprays, or topical creams (38). A condition known as “Hunan hand,” which is a form of contact dermatitis, has been noted in workers handling peppers (39). When applied to glabrous lips or tongue, capsaicin elicits burning pain, the intensity of which corresponds with the degree of increased blood flow and temperature induced by capsaicin (40). On the one hand, capsaicin has also been shown to be an effective topical treatment for hemodialysis-induced pruritus (i.e., itching) in patients with end-stage renal disease (41). On the other hand, topical application of capsaicin was not effective in serotonin-induced itching in healthy volunteers (42).

Topical application of capsaicin has been used in cancer patients in the management of long-term neuropathic pain resulting from surgery (43). Patients received 8 weeks of a 0.075% capsaicin cream (4 times per day) followed by 8 weeks of an identical-looking placebo cream or vice versa. Most patients preferred the capsaicin treatment over the placebo in spite of some toxic side effects that included coughing and burning and redness of the skin (43). Oral capsaicin in a candy (taffy) vehicle produced substantial temporary pain reduction in 11 patients with oral mucositis pain from cancer therapy (44). However, capsaicin was not effective in relieving pain accompanying HIV-associated distal symmetrical peripheral neuropathy (45).

In a review of double-blind placebo-controlled trials pooled for analysis of neuropathic conditions or musculoskeletal conditions, topically applied capsaicin exhibited moderate-to-poor efficacy (46). Notably, local administration of capsaicin resulted in adverse events or even in an increase of pain above tolerable levels in about one third of patients suffering from musculocutaneous or neuropathic pain (46). In addition, at least one coronary vasospasm and acute myocardial infarction, reportedly induced by the use of a topical capsaicin patch to relieve lower back pain, has been documented (47).

Cocarcinogenic Effect of Capsaicin

We recently reported that capsaicin has a cocarcinogenic effect on TPA-promoted skin carcinogenesis in vivo and is mediated not only through the transient receptor potential vanilloid subfamily member 1 (TRPV1), but also through the tyrosine kinase epidermal growth factor receptor (EGFR). Even though blockade of the TRPV1 has been suggested as a therapeutic approach to pain relief, TRPV1 is a widely expressed protein with a function that might be critical in various nonneuronal physiologic conditions. The EGFR is a receptor tyrosine kinase that is overexpressed in many human epithelial cancers and is a potential target for anticancer drugs. We showed that TRPV1 interacts with the EGFR, leading to EGFR degradation. The TRPV1 is the first membrane receptor shown to have a tumor-suppressing effect associated with the downregulation of another membrane receptor. Notably, the absence of TRPV1 in mice resulted in a striking increase in skin carcinogenesis. The data suggest that, although a great deal of interest has focused on TRPV1 as a target for pain relief, the chronic blockade of this pain receptor might increase the risk for skin cancer development (48).

Furthermore, we showed that topical application of capsaicin on the dorsal skin of DMBA-initiated and TPA-promoted TRPV1 wild-type (WT) and TRPV1 knockout (KO) mice not only induced skin tumors in WT mice, but also more and larger skin tumors in TRPV1/KO mice, suggesting an additional TRPV1-independent mechanism. Cyclooxygenase-2 (COX-2) was highly elevated by capsaicin treatment in tumors and murine embryonic fibroblasts from TRPV1/KO mice. Inhibitors of EGFR/MAP/ERK kinase signaling suppressed TPA/capsaicin–induced COX-2 expression in TRPV1/KO cells, indicating that activation of EGFR and its downstream signaling is involved in COX-2 elevation. Capsaicin induced a further induction of TPA-increased COX-2 expression in EGFR/WT cells, but not in EGFR/KO cells. TPA/capsaicin cotreatment caused EGFR tyrosine phosphorylation and activated EGFR downstream signaling, including extracellular signal regulated kinases (ERK) and Akt in EGFR/WT, but not EGFR/KO cells. Specific inhibition of EGFR and TRPV1 indicated that capsaicin-induced ERK activation in A431 cells was dependent on EGFR, but not TRPV1. Overall, these observations indicate that capsaicin not only acts through the TRPV1 as a cocarcinogen in TPA-induced skin carcinogenesis, but also exerts these effects by activating the EGFR and COX-2 (49).

The toxicity and safety of capsaicin and related compounds have been evaluated, and results have been presented in at least one international report (50). A major, but predictable, conclusion was that capsaicin is a skin irritant even at low concentrations. Skin irritation and other tumor-promoting effects of capsaicin seem to be mediated mainly through interaction with the TRPV1, and the authors suggested that a potent tumor promoter might also be a moderate-to-severe skin irritant. Thus, a limitation on capsaicin content in topical applications that would significantly reduce its skin irritation potential might be expected to lessen concerns relating to tumor promotion potential (50). Our results seem to support this recommendation. We conclude that capsaicin alone is not a carcinogen because topical application of capsaicin to the dorsal skin of mice in the absence of a tumor promoter produced no skin cancers. However, the data also suggest that total blockade of the TRPV1 for pain relief or chronic, long-term topical application of capsaicin might increase the risk of skin cancer, especially in the presence of a tumor promoter, such as, for example, sunlight.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Grant Support

This work was supported by The Hormel Foundation and NIH grants CA077646, CA111536, CA120388, R37CA081064, and ES016548.