Oleanolic acid induces p53-dependent apoptosis via the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice

Abstract

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), U87 (human glioblastoma), normal murine liver cell (BNL CL.2) and human foreskin fibroblast cell lines (Hs 68). The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA did not exhibit toxicity in BNL CL. 2 and Hs 68 cell lines in our experiments. OA, at 100 µg/mL, increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, Bax, PARP-1 and caspase-3 expression in DU145, MCF-7 and U87 cell lines. OA-treated DU145 cells were arrested in G2 because of the activation of p-AKT, p-JNK, p21 and p27, and the decrease in p-ERK, cyclin B1 and CDK2 expression; OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin D1, CDK4, cyclin E, and CDK2; and OA-treated U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p-AKT, p21, and p27, and the decrease in cyclin D1, CDK4, cyclin E and CDK2. Thus, OA arrested the cell cycle at different phases and induced apoptosis in cancer cells. These results suggested that OA possibly altered the expression of the cell cycle regulatory proteins differently in varying types of cancer.

Mechanistic investigations of antitumor activity of a Rhodamine B‑oleanolic acid derivative bioconjugate

“…1), a pentacyclic triterpenoid widely found in plants, whose cytotoxic effect has been tested in numerous tumor cell lines, such as lung cancer (3), breast cancer (4), colon cancer (5) and melanoma cell lines (6), is considered a promising anticancer drug. Insights have been gained with regard to the complexity of mechanisms underlying the antitumor effect of OA, as follows: i) induction of an increased expression of p53 tumor protein, cytochrome c, caspase-3 apoptosis-promoting protein and Bax; ii) triggering of mitochondrial mediated apoptosis; iii) inhibition of Akt, mTOR and S6K protein expression; iv) cell cycle arrest in different phases in a cancer type-depen-Mechanistic investigations of antitumor activity of a Rhodamine B-oleanolic acid derivative bioconjugate dent manner by altering the expression of regulatory cell cycle proteins (7)(8)(9); v) antioxidant activity by exerting scavenging effect against superoxide anion, hydroxyl radical, nitric oxide and hydrogen peroxide and also by increasing the ferrous iron chelating activity (10); and vi) inhibition of angiogenesis in a dose-dependent manner (11).…”

<p>Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity</p>

“…As revealed in Figure 7, OA increases the apoptosis through Bad overexpression by suppressing the mTOR pathway activation via AMPK pathway,11 which inhibits mTOR phosphorylation to suppress protein synthesis in cancer cells 55. OA also significantly enhances the antitumor activity via p53-induced caspase-mediated pro-apoptotic signaling pathway 56. As shown in Figure 7, p53 pathway proapoptotic proteins, such as p53, Bax, cytochrome C, and caspase-3 were upregulated, while the anti-apoptotic Bcl-2 expression was decreased.…”

Red Beetroot and Betalains as Cancer Chemopreventative Agents

“…Cell cycle analysis revealed that oleanolic acid induced cell cycle arrest in HepG2 cells at the sub-G1 (apoptotic) phase of the cell cycle, in a dose-dependent manner [39]. Kim et al [59] showed that the compound increased apoptosis and decreased cell cycling in xenotransplanted prostate DU145 cells. Activation of the genes p53, Bax, and Akt was observed, while cyclin B1, cyclin E, cdk2, p -erk, and c-jun activities were down-regulated.…”