The Anticancer Activities of Natural Terpenoids That Inhibit Both Melanoma and Non-Melanoma Skin Cancers

Abstract

The prevalence of two major types of skin cancer, melanoma and non-melanoma skin cancer, has been increasing worldwide. Skin cancer incidence is estimated to rise continuously over the next 20 years due to ozone depletion and an increased life expectancy. Chemotherapeutic agents could affect healthy cells, and thus may be toxic to them and cause numerous side effects or drug resistance. Phytochemicals that are naturally occurring in fruits, plants, and herbs are known to possess various bioactive properties, including anticancer properties. Although the effects of phytochemicals are relatively milder than chemotherapeutic agents, the long-term intake of phytochemicals may be effective and safe in preventing tumor development in humans. Diverse phytochemicals have shown anti-tumorigenic activities for either melanoma or non-melanoma skin cancer. In this review, we focused on summarizing recent research findings of the natural and dietary terpenoids (eucalyptol, eugenol, geraniol, linalool, and ursolic acid) that have anticancer activities for both melanoma and non-melanoma skin cancers. These terpenoids may be helpful to protect skin collectively to prevent tumorigenesis of both melanoma and nonmelanoma skin cancers.

Keywords: melanoma; natural terpenoids; non-melanoma skin cancer; phytochemicals; skin cancer.

Figure 1

Schematic of the mechanisms involved in the anti-skin-cancer effects of eucalyptol. In NMSC, eucalyptol functions as an AhR agonist and suppresses UVB-induced COX-2 and PGE₂, and inhibits carcinogenesis. By upregulating P53, eucalyptol increases apoptotic markers, such as Bax, cytochrome c, caspase-3, caspase-9, and decreases Bcl-2 that leads to apoptosis and blocks cell proliferation. G2/M cell cycle by eugenol also leads to apoptosis. Inhibition of the PI3K/Akt/mTOR pathway reduces the metastasis of NMSC, and it is also involved in the anti-metastasis of melanoma, increases epithelial markers, and decreases mesenchymal markers. ↓: decrease in expression; ↑: increase in expression; $\times$ (red): arrest in cell cycle.

Figure 2

Schematic of the mechanisms involved in the anti-skin-cancer effects of eugenol. In NMSC, eugenol inhibits NF-κB, repressing inflammation markers iNOS, COX-2, IL-6, TNF-$\mathsf{\alpha }$, and PGE₂. Inhibition of NF-κB induces P53 and P21^WAF1, which leads to an increase in the Bax/Bcl ratio and active caspase-3, inducing apoptosis. In melanoma, eugenol suppresses E2F1 expression that causes the S-phase cell cycle arrest, leading to apoptosis. Eugenol is also able to inhibit metastasis, but the underlying mechanisms have yet to be elucidated. ↓: decrease in expression; ↑: increase in expression; $\times$ (red): arrest in cell cycle.

Figure 3

Schematic of the mechanisms involved in the anti-skin-cancer effects of geraniol. In NMSC, geraniol inhibits LOX-5 and hyaluronidase activity, which reduces metastasis and proliferation. Decreased COX-2 expression and inhibition of the Ras/Raf/ERK1/2 pathway is involved in the anti-proliferation of NMSC by geraniol. Geraniol also induces G0/G1 cell cycle arrest in NMSC that leads to apoptosis. In melanoma, HMG-CoA reductase inhibition is found to cause apoptosis. ↓: decrease in expression; ↑: increase in expression; $\times$ (red): arrest in cell cycle.

Figure 4

Schematic of the mechanisms involved in the anti-skin-cancer effects of linalool. Linalool suppresses the proliferation markers, including NF-κB, TNF-α, IL-6, COX-2, VEGF, TGF-β1, Bcl-2, inhibiting the proliferation of NMSC. In melanoma, linalool increases caspase-3, leading to apoptosis and decreasing proliferation. Linalool also decreases the mesenchymal markers, vimentin, MMP2, and MMP9, and increases the epithelial marker, E-cadherin, inhibiting metastasis of melanoma.

Figure 5

Schematic of the mechanisms involved in the anti-skin-cancer effects of ursolic acid. UA restores the expression of Nrf2 in NMSC and this upregulates HO-1, NQO-1, and UGT, preventing neoplastic transformation. UA also functions as an ROS scavenger, preventing DNA damage and inducing apoptosis by increasing active caspase-3 and caspase-7. In melanoma, UA induces apoptosis by increasing P53, Bax, caspase-3, caspase-8, and decreasing Bcl-2. UA downregulates NF-κB, c-FOS, ATF-2, and CREB, and induces the S-phase cell cycle arrest, which also leads to apoptosis. Inflammation is reduced by UA with decreased inflammatory markers, including IL-6, TNF-$\mathsf{\alpha }$, IL-1$\mathsf{\beta }$, and granulocyte-macrophage colony-stimulating factor (GM-CSF). ↓: decrease in expression; ↑: increase in expression; $\times$ (red): arrest in cell cycle.