Involvement of the PI3K/AKT Intracellular Signaling Pathway in the AntiCancer Activity of Hydroxytyrosol, a Polyphenol from Olea europaea, in Hematological Cells and Implication of HSP60 Levels in Its Anti-Inflammatory Activity

Abstract

Hydroxytyrosol (HT), the main representative of polyphenols of olive oil, has been described as one of the most powerful natural antioxidants, also showing anti-inflammatory, antimicrobial, cardioprotective and anticancer activity in different type of cancers, but has been little studied in hematological neoplasms. The objective of this work was to evaluate the anticancer potential of HT in acute human leukemia T cells (Jurkat and HL60) and the anti-inflammatory potential in murine macrophages (Raw264.7). For this, cytotoxicity tests were performed for HT, showing IC50 values, at 24 h, for Jurkat, HL60 and Raw264.7 cells, of 27.3 µg·mL−1, 109.8 µg·mL−1 and 45.7 µg·mL−1, respectively. At the same time, HT caused cell arrest in G0/G1 phase in both Jurkat and HL60 cells by increasing G0/G1 phase and significantly decreasing S phase. Apoptosis and cell cycle assays revealed an antiproliferative effect of HT, decreasing the percentage of dividing cells and increasing apoptosis. Furthermore, HT inhibited the PI3K signaling pathway and, consequently, the MAPK pathway was activated. Inflammation tests revealed that HT acts as an anti-inflammatory agent, reducing NO levels in Raw264.7 cells previously stimulated by lipopolysaccharide (LPS). These processes were confirmed by the changes in the expression of the main markers of inflammation and cancer. In conclusion, HT has an anticancer and anti-inflammatory effect in the cell lines studied, which were Raw264.7, Jurkat, and HL60, and could be used as a natural drug in the treatment of liquid cancers, leukemias, myelomas and lymphomas.

Olive Polyphenol Oxidase Gene Family

“…The main phenolic components of VOO are the secoiridoid derivatives of hydroxytyrosol (HTy) and tyrosol (Ty), with the hydroxytyrosol-containing phenolic components having the highest biological activities. They are the most effective in preventing chronic diseases due to their superior ability to reduce chronic inflammation and oxidative damage and their potent anti-proliferative activity [ 3 , 4 ]. In this sense, scientific evidence on the health benefits of HTy has led the European Food Safety Authority (EFSA) to approve a health claim that states “olive oil polyphenols contribute to the protection of blood lipids from oxidative stress”.…”

Computational investigation of the functional landscape of the protective role that Extra Virgin Olive Oil consumption may have on Chronic Lymphocytic Leukemia

“…Interestingly, it is known that CLL cells are vulnerable to sudden and continuous activation of the PI3K/AKT signaling pathway [40]. Additionally, it has been reported that hydroxytyrosol inhibits the PI3K signaling pathway in acute human leukemia T cells (Jurkat and HL60) [55]. Regarding the shortlisted GO-BPs, 3 out of 16 were also highlighted from our computational verification meta-analysis: regulation of apoptotic process (GO:0042981), innate immune response (GO:0045087)and DNA metabolic process (GO:0006259).…”

Olea europaea Leaf Phenolics Oleuropein, Hydroxytyrosol, Tyrosol, and Rutin Induce Apoptosis and Additionally Affect Temozolomide against Glioblastoma: In Particular, Oleuropein Inhibits Spheroid Growth by Attenuating Stem-like Cell Phenotype

“…HT is the second major OLE structure phenol [ 37 ], where the degradation of OL leads to the majority of its production [ 43 ]. The antiproliferative, proapoptotic, and anti-inflammatory properties of HT were recently evidenced in human neuroblastoma cells (SH-SY5Y), acute human leukemia T-cells (Jurkat and HL60), and colorectal cancer cells (HCT116 and LoVo) [ 44 , 45 , 46 ]. In this study, HT led to 50% inhibition of GB cell proliferation in the lowest concentration among all investigated phenolics of OLE by arresting the cell cycle in the S and G2/M phases, demonstrating its robust preventive capacity against GB.…”