Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma

Abstract

Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA), being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR), in human soft tissue sarcoma cells. UA (5–50 μM) strongly inhibited (up to 80%) the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6–9 h) strongly blocked the survival AKT/GSK3β/β-catenin signalling pathway, which led to a concomitant reduction of the anti-apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10–15 μM) enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR-induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS.

Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

“…In this regard, UA seems to be an interesting target to develop new formulations to be used in human health, because different reports demonstrated its multivalent activities against pathological conditions. UA was demonstrated to be active against different tumor cell lines (Chuang et al., 2016, Aguiriano-Moser et al., 2015, Kim and Moon, 2015), its anti-tumoral effect being associated to apoptosis induction by intrinsic and extrinsic pathways of death (Li et al., 2014, Meng et al., 2015, Zhang et al., 2016, Villar et al., 2016). …”

Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling

“…Studies have identified that the growth-inhibitory function of p21 is closely related to its intracellular localization [ 13 , 31 ], whereas cytoplasmic re-localization resulting from phosphorylation of p21 was associated with anti-apoptotic behaviors [ 32 ]. P-AKT was able to phosphorylate p21 at T145, and transfer p21 to the cytoplasm, where it promotes cell growth and suppresses cell apoptosis [ 12 , 33 , 34 ].…”

Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives

“…The in vivo anticancer activity of betulinic acid was identified using xenograft models [ 10 , 11 ]. The ursolic acid can also induce apoptosis, autophagy, and cell cycle arrest through various pathways, such as inhibition of DNA replication, stimulation of reactive oxygen species (ROS) production, and affecting the balance between proapoptotic and antiapoptotic proteins [ 6 , 12 , 13 ].…”