Ursolic acid: a natural modulator of signaling networks in different cancers

Abstract

Incidence rate of cancer is estimated to increase by 40% in 2030. Furthermore, the development of resistance against currently available treatment strategies has contributed to the cancer-associated mortality. Scientists are now looking for the solutions that could help prevent the disease occurrence and could provide a pain-free treatment alternative for cancers. Therefore, efforts are now put to find a potent natural compound that could sever this purpose. Ursolic acid (UA), a triterpene acid, has potential to inhibit the tumor progression and induce sensitization to conventional treatment drugs has been documented. Though, UA is a hydrophobic compound therefore it is usually chemically modified to increase its bioavailability prior to administration. However, a thorough literature indicating its mechanism of action and limitations for its use at clinical level was not reviewed. Therefore, the current study was designed to highlight the potential mechanism of UA, its anti-cancer properties, and potential applications as therapeutic compound. This endeavour is a valuable contribution in understanding the hurdles preventing the translation of its potential at clinical level and provides foundations to design new studies that could help enhance its bioavailability and anti-cancer potential for various cancers.

Keywords: Anti-cancer potential; Cell signaling; Drug resistance; Natural compound; Ursolic acid.

Fig. 1

Synthesis of ursolic acid. a The process of ursolic acid synthesis begins with the conversion of glucose into acetate. Acetate is eventually converted into acetyl-CoA and mevalonate. b Several intermediate metabolites are produced in the process, mediated by several enzymes. c Squalene epoxidase (SE) finally produces 2,3-oxidosqualene that is converted into d α-amyrin and β-amyrin. Enzyme 1aCYP716A40 then produce ursolic acid from α-amyrin

Fig. 2

Mechanism of action of Ursolic acid in cancers. Ursolic acid targets numerous molecular players of different cell signaling cascades to promote its anti-cancer potential. It inhibits the activity of Akt, mToR, and ERK, and halts the receptor tyrosine kinase interaction with their respective ligands. It promotes the functioning of Bcl2, BAX, Cytochrome C, and KEAP1. It down-regulates the transcription of MMPs, PD-L1, and VEGF and up-regulates the expression of P27, P21, and Bcl2

Fig. 3

Different targets of ursolic acid in different cancers. Arrow pointing down indicates down-regulation or decrease in activity and arrow pointing up represents increased activity or up-regulation