The search throughout nature for phytomolecules that may be effective for combating cancer extends to terpenes and terpenoids. In a previous blog, we discussed how plant-derived mono- and sesquiterpenoids have been studied for their anticancer properties, specifically regarding melanoma. This blog covers di- and triterpenoids.
How Can Diterpenoids Treat Cancer?
Similar to monoterpenoids, diterpenoids are made up of two carbon isoprenoid units and have shown promise in the treatment of various cancers. Andrographolide, for example, common to a plant called green chiretta, has promise as an antibacterial, antiviral, anti-inflammatory, anti-diabetic, and anti-cancer organic material. [1] A 5 µg/g dose of andrographolide led to tumor volume decrease in mice and is now showing similar potential in human trials. [2,3] It is believed that the γ-butyrolactone ring in andrographolide is what contributes to the high cytotoxicity.
Another promising diterpenoid is carnosic acid, a molecule found in sage and rosemary species, that has indicated the potential to stop the spread of melanoma cells by increasing the amount of a tissue inhibitor called metalloproteinase. [4] Also, triptolide, from the Chinese medical herb known as thunder duke vine, has been studied in breast cancer, rectal cancer, and melanoma. [5] Triptolide can also limit the spread of melanoma, but it works on protein regulators to limit transcription and effector proteins. [6] Finally, there is a molecule inelegantly known as 7,13-diacetyl-5-angeloyl-20-nicotinyl-3-propionyl-1,2,6,7-tetrahydroingenol or DANPT, which promotes cytotoxicity and cellular arrest through oxidative stress. [7]
The Effects of Triterpenoids
Triterpenoids are the most complex chemical terpenes, and in turn, they provide more complex benefits. Ursolic acid and its isomer oleanolic acid are found in apple peels, bilberries, cranberries, elderflower, lavender, oregano, and thyme. When combined with ultraviolet radiation in skin melanoma patients, ursolic acid increased oxidative stress and the potential for mitocondrial membrane collapse. [8] This, in turn, leads to higher potential for apoptosis (cell death) in early-stage patients.
Cucurbitacins are another form of triterpenoids that naturally occur in plants like pumpkins, melons, and cucumbers. These triterpenoids create a natural defense in plants, and likewise have demonstrated antitumor effects in cervical, lung, colon, bladder and prostate cancer. [1,9] Similarly, betulinic acid leads to anticancer properties through mitochondrial disruption through decreased oxygen consumption and extracellular acidification. [10]
Putting It All Together
Though melanoma only accounts for 0.6% of all cancer-related deaths, it is the leading cause of death from skin cancer. Due to the high flexibility and potential for spread, melanoma remains one of the most difficult cancers to treat and fully remove. In addition to Food & Drug Administration approved treatment methods like excision or immunotherapy, there is a potential to supplement these treatments with plant-based terpenes/terpenoids. Depending on the nature and stage of development of the melanoma, there are many terpenoids that have the potential to augment traditional treatment methods in different ways. The appropriate course of action depends on a case-by-case basis.
References
[1] Kłos P, Chlubek D. Plant-derived terpenoids: A promising tool in the fight against melanoma. Cancers (Basel). 2022;14(3):502. [journal impact factor = 6.639; times cited = 0][2] Zhang QQ, Zhou DL, Ding Y, et al. Andrographolide inhibits melanoma tumor growth by inactivating the TLR4/NF-κB signaling pathway. Melanoma Res. 2014;24(6):545-555. [journal impact factor = 3.599; times cited = 32]
[3] Liu G, Chu H. Andrographolide inhibits proliferation and induces cell cycle arrest and apoptosis in human melanoma cells. Oncol Lett. 2018;15(4):5301-5305. [journal impact factor = 2.967; times cited = 14]
[4] Park SY, Song H, Sung MK, Kang YH, Lee KW, Park JH. Carnosic acid inhibits the epithelial-mesenchymal transition in B16F10 melanoma cells: a possible mechanism for the inhibition of cell migration. Int J Mol Sci. 2014;15(7):12698-12713. [journal impact factor = 5.923; times cited = 24]
[5] Deng Y, Li F, He P, et al. Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition. Mol Carcinog. 2018;57(6):807-814. [journal impact factor = 4.784; times cited = 21]
[6] Jao HY, Yu FS, Yu CS, et al. Suppression of the migration and invasion is mediated by triptolide in B16F10 mouse melanoma cells through the NF-kappaB-dependent pathway [published correction appears in Environ Toxicol. 2016 Aug;31(8):1028-9]. Environ Toxicol. 2016;31(12):1974-1984. [journal impact factor = 4.119; times cited = 9]
[7] Fallahian F, Ghanadian M, Aghaei M, Zarei SM. Induction of G2/M phase arrest and apoptosis by a new tetrahydroingenol diterpenoid from Euphorbia erythradenia Bioss. in melanoma cancer cells. Biomed Pharmacother. 2017;86:334-342. [journal impact factor = 6.529; times cited = 8]
[8] Lee YH, Wang E, Kumar N, Glickman RD. Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV-VIS broadband radiation. Apoptosis. 2014;19(5):816-828. [journal impact factor = 4.677; times cited = 29]
[9] Ahmed MS, Halaweish FT. Cucurbitacins: potential candidates targeting mitogen-activated protein kinase pathway for treatment of melanoma. J Enzyme Inhib Med Chem. 2014;29(2):162-167. [journal impact factor = 4.31; times cited = 25]
[10] Coricovac D, Dehelean CA, Pinzaru I, et al. Assessment of betulinic acid cytotoxicity and mitochondrial metabolism impairment in a human melanoma cell line. Int J Mol Sci. 2021;22(9):4870. [journal impact factor = 5.923; times cited = 5]
