Nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, are common neoplasms worldwide and are the most common cancers in the United States. Standard therapy for cutaneous neoplasms typically involves surgical removal. However, there is increasing interest in the use of topical alternatives for the prevention and treatment of nonmelanoma skin cancer, particularly superficial variants. Botanicals are compounds derived from herbs, spices, stems, roots, and other substances of plant origin and may be used in the form of dried or fresh plants, extracted plant material, or specific plant-derived chemicals. They possess multiple properties including antioxidant, anti-inflammatory, and immunomodulatory properties and are, therefore, believed to be possible chemopreventive agents or substances that may suppress or reverse the process of carcinogenesis. Here, we provide a review of botanical agents studied for the treatment and prevention of nonmelanoma skin cancers.
Nonmelanoma skin cancer (NMSC) is common worldwide and includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Approximately two to three million NMSCs occur globally each year [
Traditional recommendations for prevention of NMSC include generous use of sunscreens and avoidance of chronic or intense ultraviolet (UV) exposure. Conventional therapy for NMSCs involves surgical removal or directed topical therapies in the most superficial subtypes of NMSC. However, there is increasing interest in alternative, noninvasive treatments and preventative measures in recent years, specifically in the use of naturally occurring botanicals. Botanicals are a group of compounds derived from herbs, spices, stems, roots, and other substances of plant origin and may be used in the form of dried or fresh plants or extracted plant material [
Here, we review botanical agents that have been used for the treatment and prevention of NMSCs. Botanical agents studied in humans as well as agents investigated in preclinical trials are reviewed.
We conducted a search of the PubMed and Embase databases of articles published from 1990 to 2013 to include the most recent literature. Articles containing combinations of MeSH terms “nonmelanoma skin cancer,” “basal cell carcinoma,” “squamous cell carcinoma,” “complementary therapies,” “plant preparations,” “edible plants,” “herbal medicine,” “antineoplastic agents,” “phytogenic,” and “botanical” were reviewed. Based on the initial review using these terms, botanical agents and extracts identified as having possible effects on NMSC treatment and prevention through studies, reviews, and case reports, were reviewed. The search was limited to articles in English and initially resulted in 91 articles. The article abstracts were reviewed for relevance to the subject matter of treatment and prevention of UV light-induced NMSCs, BCCs, and SCCs, using botanical agents. We examined reference lists to identify any missing articles, and a total of 74 articles were included in this review. We included only botanical agents that have been investigated in more than one study and/or have been reported in more than one case.
Summary of the effects of botanical agents studied in humans.
Botanical agent | Source | Efficacy | Histopathological |
References |
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Ingenol mebutate |
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Demonstrated clinical response (tumor clearance) for BCCs and SCCs. | No | [ |
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Hypericin |
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Reported clinical response for BCCs and SCCs to hypericin and photodynamic therapy in one study [ |
Yes | [ |
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Coffee |
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Coffee consumption was related to decreased prevalence of NMSC in two studies [ |
No | [ |
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Tea |
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Inconsistent results in human studies. Regular tea consumption was associated with reduced risk of SCC and BCC incidence in one study [ |
No | [ |
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Escharotic botanical agents | Black salve |
Cases reported no improvement of BCC and extensive skin necrosis with black salve application [ |
No | [ |
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Paclitaxel |
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In vitro study demonstrated topical paclitaxel increased antiproliferative activity in a squamous cell carcinoma model [ |
No | [ |
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Beta-carotene |
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No efficacy for NMSCs. | No | [ |
Summary of the effects of botanical agents studied in mice that have also been studied in humans.
Botanical agent | Source | Efficacy | References |
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Hypericin |
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The combination of hypericin and photodynamic therapy had poor efficacy in one mouse model [ |
[ |
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Tea |
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Animal studies demonstrate catechins have antitumor effects in mice [ |
[ |
Ingenol mebutate is an extract from the
Furthermore, a phase IIa randomized, vehicle-controlled study of 60 patients evaluated the safety (primary endpoint) and efficacy (secondary endpoint) of ingenol mebutate gel for superficial basal cell carcinoma, with a lesion size of 4–15 mm. In this study, Siller et al. randomized patients to Arm A, treatment on days 1 and 2, or Arm B, treatment on days 1 and 8 [
A prospective pilot study by Kacerovská et al. investigated the use of an extract of
Coffee derives from seeds of the
More recently, Abel et al. performed a cross-sectional analysis of 93,676 Caucasian women in the Women’s Health Initiative Observational Study to determine the relationship between consumption of coffee on a daily basis with the prevalence of NMSCs [
Dried and unfermented
A study by Lu et al. demonstrated that when hairless mice were irradiated with UVB light twice weekly for a total of 20 weeks followed three weeks later by treatment with topical caffeine or EGCG once daily for five days over 18 weeks, the number of cutaneous tumors decreased [
Expanding on the animal studies, the use of green tea and its ingredients have been studied in humans. Asgari et al. performed a case-control study of 415 cases from the Kaiser Permanente Northern California database with pathology-verified SCC in 2004 to determine the association between tea consumption, containing
Rees et al. performed a case control study to determine the relationship between regular tea consumption, defined as one cup daily for one month, and the incidence of BCCs and SCCs [
In addition to oral consumption of tea, topical tea application was reported in a 47-year-old female with basal cell nevus syndrome. She used green tea body wraps once per month for a year without any new BCCs developing in that time. The ingredients in the gel wrap included green tea primarily, as well as other plant extracts—ginger oil, algae, calendula oil, and mustard oil [
Black salve, a combination of botanical agents, and bloodroot are two escharotic botanical agents that have been described in isolated case reports for their use in NMSCs. One case reported a 63-year-old male with a BCC confirmed by histopathology and located below the right eye [
Paclitaxel is a plant alkaloid derived from the bark of the Pacific yew tree
Paclitaxel has also been reported in two cases for the treatment of BCC. A 60-year-old male with a sclerosing BCC on the right eyelid refractory to local therapy, surgery, radiation, and six cycles of cisplatin and capecitabine was subsequently treated with paclitaxel 175 milligrams per square meter (mg/m2) intravenously every 21 days for a total of 15 cycles. Complete response with elimination of the BCC was achieved after 12 cycles. The patient tolerated the treatment well and remained in complete remission documented clinically 13 months from his first cycle of treatment [
Beta carotene is a pigment found in a variety of plants, including carrots and richly hued vegetables. Many studies have demonstrated that a high consumption of vegetables and fruits with a high concentration of beta carotene has an inverse association with the risk of cancer [
Summary of the effects of botanical agents investigated only in preclinical studies.
Botanical agent | Source | Efficacy | References |
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Curcumin |
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Curcumin inhibits skin tumor carcinogenesis in mice. | [ |
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Genistein | Soy, Greek sage, Greek oregano, and gingko biloba extract | Genistein inhibits skin tumor carcinogenesis in mice. | [ |
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Proanthocyanidin | Grape seed | Grape seed proanthocyanidins demonstrated anticarcinogenic effects against ultraviolet B-induced skin tumors in mice. | [ |
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Lycopene | Various plants with red pigment | Lycopene prevents photodamage in mice and humans, suggesting potential for possible prevention of NMSC. | [ |
Curcumin is a spice that originates from the root of the
Genistein is a flavonoid found in soy, Greek sage, Greek oregano, and ginkgo biloba extract and is specifically a major isoflavone in soybeans. Studies have shown that genistein have antioxidant and anticarcinogenic activity in the skin [
Grape seeds contain proanthocyanidins, a group of polyphenols that have been found to possess anti-inflammatory and antioxidant properties [
Lycopene is a carotenoid that provides the red pigmentation found in tomatoes, guava, watermelon, pink grapefruit, papaya, rosehips, and other vegetables and fruits. Though it is a phytochemical that lacks provitamin A activity, lycopene has been studied for its anticarcinogenic and antioxidant activity for breast [
Silymarin is a flavonoid derived from
Ingenol mebutate, hypericin, coffee, tea, black salve, bloodroot, paclitaxel, and beta-carotene have been studied for their effects on NMSC in humans or have been reported to be used in humans with BCCs and SCCs. Clinical trials assessing the effectiveness of ingenol mebutate on BCCs and SCCs and case reports with patients using paclitaxel for BCCs suggest efficacy of these agents for treating NMSCs in humans. Despite favorable results, more human studies are needed to assess the chemopreventive and therapeutic effects of these botanical agents. In particular, prospective trials with efficacy as the primary outcome are still needed. Furthermore, black salve and bloodroot were reported to be more harmful than therapeutic. Participants taking beta carotene showed no difference in skin cancer rate compared to the control groups. Although clinical response has been reported using hypericin with photodynamic therapy, coffee, and tea in humans with NMSCs, there is no consensus as to the effectiveness of these agents based on the results of the studies. Finally, it is important to note that in short studies, such as the study of ingenol mebutate by Siller et al. that lasted only 12 weeks [
Although histopathological evaluation of clearance is the gold standard, future studies should consider additional incorporation of confocal microscopy. Confocal microscopy may have a role in noninvasively assessing superficial BCC recurrence [
Five botanical agents appear to have potential for anticarcinogenesis based on preclinical studies. Curcumin, genistein, grape seed proanthocyanidin, and silymarin have demonstrated reduction in UV-induced skin cancers in mice, and lycopene has been shown to prevent photodamage in mice and humans. However, one botanical agent that has been studied for its effects on NMSCs, beta carotene, does not appear to be effective against skin cancer. Curcumin, genistein, grape seed, lycopene, and silymarin have not yet been studied in humans for the treatment or prevention of NMSC.
An important characteristic that is highly important for topical delivery of botanical agents is their hydrophilicity and lipophilicity. Phytochemical subgroups that tend to be more hydrophilic, such as polyphenol, may not penetrate the stratum corneum well. This may explain why topical polyphenols do not seem to be as efficacious as oral/systemic delivery. On the other hand, topical delivery of more lipophilic phytochemicals, such as ingenol or silymarin, will be able to penetrate the stratum corneum more effectively. One option in conducting studies with agents that have a lower partition coefficient will be to facilitate their transit through the stratum corneum through penetration enhancers such as liposomes, iontophoresis, sonophoresis, or microneedle technology. Our suggestion for future evaluation of topical botanicals is that investigators take the octanol-water partition coefficient or the mode of extraction of the extract into account in designing future studies. For example, a nonaqueous extract or a phytochemical with a high partition coefficient may not require a penetration enhancer; on the other hand, it would be prudent to consider the use of penetration enhancers when studying aqueous extracts or phytochemicals with low partition coefficients.
In vitro and in vivo models have been developed with the hypothesis that natural products rich in complex chemicals that have been shown to induce apoptosis in animal models of chemoprevention may therefore possess the ability to arrest the cell cycle at different stages and, therefore, control the proliferation of cancer cells. Botanical agents have been studied, and some have been reported to have favorable effects against NMSC.
In this review, we have included a variety of botanical agents that have been studied or reported for the treatment of NMSCs. A limitation of this review is that we did not include botanical agents that were reported in a single case or a single preclinical study. However, we have provided an up-to-date and concise review of botanical agents used in NMSC that is currently found in the literature. Although the limited preclinical data and clinical data available in the literature demonstrate favorable effects of some botanical agents on NMSC, for now, surgical therapy is the preferred mode of treatment for high-risk NMSCs. Botanical agents may have a preventive role in the development of cutaneous malignancies and a potentially therapeutic role for carefully chosen localized NMSCs of an appropriate subtype. The topical use of some botanical extracts and phytochemicals in the treatment of NMSC is promising. However, more studies, both preclinical and clinical, are needed to make more definitive conclusions regarding safety and efficacy.
Ms. Wong, Dr. Sivamani, and Dr. Fazel have no conflict of interests to report.