Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

Abstract

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.

Use of Oleuropein and Hydroxytyrosol for Cancer Prevention and Treatment: Considerations about How Bioavailability and Metabolism Impact Their Adoption in Clinical Routine

“…However, even at high concentrations, OLE and HT seem to be selectively cytotoxic for cancer cells, with no or negligible/minimal effects on non-cancer cells, as demonstrated for embryonic rat cardiomyoblasts H9c2(2-1), human breast epithelial cell line MCF-10A [ 41 , 93 ], nonmalignant human bronchial epithelial BEAS-2B cell line [ 35 ], normal colonic cell line CCD-841CoN [ 74 ], human normal liver cell line (HL-7702) [ 67 ], human normal prostate epithelial cells PWLE2 [ 86 ], human bile duct cell line HIBEpiC [ 69 ], human fibroblasts WI-38 [ 90 ], normal skin fibroblast cell line WS1 [ 74 ], human GN61 gingival fibroblasts [ 271 ], human lymphocytes [ 78 ], human PBMCs [ 24 , 25 ], and normal human fibroblasts [ 272 , 273 ]. Thus, OLE and HT are generally considered safe on the basis of experimental data, despite sporadic reports against the trend, as happened for HT, which proved to be toxic for human non-tumorigenic pancreas cells HPDE [ 80 ] and human normal prostate RWPE-1 cells [ 87 ]. The evaluation of OLE and HT safety profile in cancer patients is still pending.…”

“…Treatment of PC-3 cells with 30 μM and 100 μM HT for 24 h reduced the migration rate in a dose-dependent manner. Treatment of 22Rv1 cells with 10 μM HT reduced prostatosphere number and size after 10 days, and phosphorylation of ERK1/2, cAMP response element-binding (CREB) protein, and JNK after 24 h [ 87 ].…”

Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin

“…To determine the clonogenic capacity of 22Rv1 and PC-3 PCa cells in response to different treatments, 2000 cells were seeded into 6-well plates, as previously reported [ 52 ]. Then, after 10 days, the medium was removed, the colonies washed with PBS, stained with crystal violet solution (crystal violet at 0.05% and glutaraldehyde at 6%) for 30 min, and air-dried.…”

Anti-proliferative Effects of Hydroxytyrosol Against Breast Cancer Cell Lines Through Induction of Apoptosis

“…So far, many studies have reported anti-cancer activity of hydroxytyrosol against numerous human malignancies (12,13). In a recent study, León-González et al demonstrated that cytotoxic effect of hydroxytyrosol on prostate cancer cells was associated with regulation of key phosphorylation in ERK1/2 and AKT signaling pathways (14). In another study, Oktay and Tu grul reported that the cytotoxic effect of hydroxytyrosol could occur through induction of apoptosis and modification of ERK1/2 signaling pathways (15).…”