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. 2017 Dec;51(6):1651-1660.
doi: 10.3892/ijo.2017.4160. Epub 2017 Oct 16.

Effects of ursolic and oleanolic on SK‑MEL‑2 melanoma cells: In vitro and in vivo assays

Angela Caunii  1 , Camelia Oprean  1 , Mirabela Cristea  2 , Alexandra Ivan  2 , Corina Danciu  1 , Calin Tatu  2 , Virgil Paunescu  2 , Daniela Marti  3 , George Tzanakakis  4 , Demetrios A Spandidos  4 , Aristides Tsatsakis  5 , Razvan Susan  5 , Codruta Soica  1 , Stefana Avram  1 , Cristina Dehelean  1
Affiliations

Effects of ursolic and oleanolic on SK‑MEL‑2 melanoma cells: In vitro and in vivo assays

Angela Caunii et al. Int J Oncol. 2017 Dec.

Abstract

Among the triterpenoids, oleanolic acid (OA) and its isomer, ursolic acid (UA) are promising therapeutic candidates, with potential benefits in the management of melanoma. In this study, we aimed to examine the in vitro and in vivo anti‑invasive and anti‑metastatic activity of OA and UA to determine their possible usefulness as chemopreventive or chemotherapeutic agents in melanoma. For the in vitro experiments, the anti‑proliferative activity of the triterpenic compounds on SK‑MEL‑2 melanoma cells was examined. The anti‑invasive potential was assessed by testing the effects of the active compound on vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) adhesion to melanoma cells. Normal and tumor angiogenesis were evaluated in vivo by chicken embryo chorioallantoic membrane (CAM) assay. The two test triterpenoid acids, UA and OA, exerted differential effects in vitro and in vivo on the SK‑MEL‑2 melanoma cells. UA exerted a significant and dose‑dependent anti‑proliferative effect in vitro, compared to OA. The cytotoxic effects in vitro on the melanoma cells were determined by the examining alterations in the cell cycle phases induced by UA that lead to cell arrest in the S phase. Moreover, UA was found to affect SK‑MEL‑2 melanoma cell invasiveness by limiting the cell adhesion capacity to ICAM molecules, but not influencing their adhesion to VCAM molecules. On the whole, in this study, by assessing the effects of the two triterpenoids in vivo, our results revealed that OA had a greater potential to impair the invasive capacity and tumor angiogenesis compared with UA.

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Figures

Figure 1
Figure 1
Chemical structures of oleanolic acid and ursolic acid.
Figure 2
Figure 2
Effects of ursolic and oleanolic acid on SK-MEL-2 human melanoma cell proliferation. *p<0.05. UA, ursolic acid; OA, oleanolic acid.
Figure 3
Figure 3
Cell cycle distribution in the SK-MEL-2 cells: (A) control, (B) cells treated with 30 µM UA, and (C) cells treated with 50 µM UA. UA, ursolic acid; dip, diploid cells; ane, aneuploidy cells.
Figure 4
Figure 4
SK-MEL-2 cell adhesion to (A) VCAM and (B) ICAM substrates following treatment with UA. UA, ursolic acid; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule. *p<0.05
Figure 5
Figure 5
Effects of UA and OA on CAM assay. (A-C) Normal angiogenesis, with two doses of the test samples on ED9. (A) Blank (DMSO, 3%), (B) UA, (C) OA. (D-F) Normal angiogenesis, with four doses of the test samples on ED11. (D) Blank (DMSO, 3%), (E) UA, (F) OA. (G-I) SK-MEL-2 melanoma cells, with four doses of the test samples on ED13. (G) Control (cell medium), (H) SK-MEL-2 + UA, (I) SK-MEL-2 + OA. UA, ursolic acid; OA, oleanolic acid; CAM, chorioallantoic membrane; DMSO, dimethyl sulfoxide.
Figure 6
Figure 6
Vascular density scores induced by the test and control samples on CAM. Normal conditions and incubation with SK-MEL-2 melanoma cells. Data were assessed after four doses of UA and OA, using a 0–5 scale, by means of stereomicroscopy. CAM, chorioallantoic membrane; UA, ursolic acid; OA, oleanolic acid.
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