Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells

Abstract

Scope: Hydroxytyrosol (HT), a polyphenol from olives, is a potential anticancer agent. This study was designed to evaluate the anticancer activity of HT against prostate cancer cells, and the mechanism thereof. Methods and Results: Treatment of LNCaP and C4–2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation. This was in contrast to HT’s ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer cells-specific effect. HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4, and induction of inhibitory p21/p27. HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage and BAX/Bcl-2 ratio. It inhibited the phosphorylation of Akt / STAT3, and induced cytoplasmic retention of NF-κB, which may explain its observed effects. Finally, HT inhibited AR expression and the secretion of AR-responsive prostate-specific antigen. Conclusion: Castration-resistant prostate cancers retain AR signaling and are often marked by activated Akt, NF-κB and STAT3 signaling. Our results establish a pleiotropic activity of HT against these oncogenic signaling pathways. Combined with its non-toxic effects against normal cells, our results support further testing of HT for prostate cancer therapy.

Anticancer effects of olive oil polyphenols and their combinations with anticancer drugs

“…HTyr suppressed activation of Akt, nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways in prostate cancer (PC) cell lines, all of them being important in proliferation, invasion and metastasis of cancer cells, and progression to aggressive castration-resistant PC (37). Suppression of Akt and NF-κB pathways by HTyr was also observed in the study of human hepatocellular carcinoma (HCC), both in vitro and in vivo, in the orthotopic mouse model of human HCC (72).…”

“…Olive oil (OO) phenolic compounds exert a possible chemoprotective and anticancer activities in different types of cancer cells (23,(31)(32)(33): breast cancer (BC) (34,35), colon (36), prostate (37), melanoma (38), promyelocytic leukemia (39) and other cancer cells. Within the few last years, a growing interest in the collective effects of chemotherapeutics in combina-tion with OOPs was observed.…”

Antitumor Perspectives of Oleuropein and Its Metabolite Hydroxytyrosol: Recent Updates

“…It inhibited the phosphorylation of Akt/STAT3, and induced cytoplasmic retention of NF‐κB, which may explain its observed effects. Finally, it inhibited androgen receptor (AR) expression and the secretion of AR‐responsive prostate‐specific antigen (Zubair et al., ).…”

Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells

“…According to the literature, the effect of HT on these pathways is controversial. Some authors have pointed that HT upregulates AMPK 56 and inhibits Akt phosphorylation in tumor and non-tumor cells at 50, 100 and 200 µM [57][58][59] . However, HT has also been shown to promote Akt phosphorylation 60 .…”