ht was also effective in the reduction in cell viability of sh - sy5y cells after 72 h incubation, with mean ec50 ± s. d. = 114. 02 ± 1. 69 μm, inducing apoptosis. glioma, a neoplastic lesion arising from glial cells, is the most frequent tumor of the central nervous system, and glioblastoma multiforme accounts for the large majority of all gliomas. glioblastomas are extremely aggressive and difficult - to - treat cancers, with very modest survival expectancy. treatment of human glioblastoma cell lines a - 172 and u - 251 with 200 μm and 400 μm ole for 24 h reduced cell viability in a dose - dependent fashion, triggering apoptosis and suppressing cell migration and invasion abilities with a mechanism involving the increase in bax, mmp2, mmp9, and phospho - akt levels, the reduction in bcl - 2 protein levels, and caspase - 9 and caspase - 3 activation. in glioblastoma cell line t98g, 277. 5 μm and 555 μm ole for 24 h diminished cell viability in a dose - dependent manner. treatment with 555 μm ole strongly increased the expression of mirnas inhibiting tumor growth: mir - 181b, mir - 137, and let - 7d. on the contrary, 277. 5 μm ole increased let - 7d levels only. expression of mir - 153 was not changed by ole treatments. in this section, the most important results about less investigated malignancies are summarized. head and neck squamous cell carcinoma is the sixth most common cancer and arises from mucosal epithelium in the oral cavity, pharynx, and larynx. treatment of human cell lines tu686 and cal - 27 with 50 – 200 μg / ml ole ( ≈92. 5 – 370 μm ) significantly reduced cell viability, while no effect was elicited by concentrations ≤ 25 μg / ml ( ≈46 μm ). consistently, 25 μg / ml did not change the apoptotic rate in the mentioned cell lines, but inhibited epithelial - to - mesenchymal transition ( emt ) induced by transforming growth factor - β1 tgf - β1. the effects of ole on emt - related proteins were also verified in a in vivo model of 686ln - m2 cell line xenograft in balb / c nude mice. among gastric cancers, gastric adenocarcinoma is the most common subtype. treatment of human gastric adenocarcinoma cell line crl - 1739 with 50 – 500 μm ole for 24 h reduced cell viability in a dose - dependent fashion, with results becoming significant for values between 200 μm and 500 μm. the authors calculated that ic50 = 42 μm. as demonstrated by incubating the mentioned cell line with 200 – 500 μm ole, 24 h exposure elicited the accumulation of ros and apoptosis. seminoma is the result of germ cell malignant transformation. it is generally associated with an excellent prognosis, and may involve testicles or extra - gonadal sites. the 48 h incubation of human seminoma cell lines sem - 1 and tcam - 2 with 15 – 200 μm ole reduced cell viability in a dose - dependent manner, with ic50 = 140 μm and 50 μm for sem - 1 and tcam - 2, respectively. treatment of the mentioned cell lines with ole concentrations corresponding to their respective ic50 values produced apoptosis, the reduction in protein levels of cyclin d1 and nuclear localization of nf - κb, the increase in bax and p21, and impaired cell migratory capacities through downregulation of tgf - β1. hematological malignancies arise from the loss of hematopoietic homeostasis, and may be configured as a large category including both myeloid and lymphatic neoplasms ( leukemia, lymphoma, and multiple myeloma ) whose incidence is pretty variable at the regional level. only limited experimental evidence supporting ole and ht preventive and anti - cancer properties is available in such a context ( table 1 ). acute promyelocytic leukemia is a form of acute leukemia characterized by a chromosomal rearrangement involving pml:: rara fusion, making this malignancy sensitive to differentiating agents inducing pml - rara fusion protein degradation by targeting the rara or the pml part ( all - trans - retinoic acid and arsenic - trioxide, respectively ). in vitro, treatment of promyelocytic leukemia cell line hl - 60 with 50 – 100 μm ht reduced cell viability and triggered apoptosis, as indicated by the cleavage of parp, the activation of caspase - 3, and cytochrome c release. according to another report, 100 μm ht reduced dna synthesis in hl - 60 cells, with promotion of cell differentiation, cell accumulation in g0 / g1 phase, and apoptosis of s phase cells. the detected cytotoxic effect of ht was caused by ht - mediated h2o2 accumulation in cell culture medium, overcoming hl - 60 ability to clear ros. the accumulation of h2o2 and the extent of apoptosis were inversely correlated with cell density. as hypothesized by the authors, in their experimental setting, the first step of ht - mediated h2o2 accumulation is the auto - oxidation of ht by o2, with production of the corresponding o - quinone and superoxide o2; the process is accelerated by sod. these findings were confirmed in a study using an ht - rich natural extract of the olive pulp as a source of ht. effects of ht on cell cycle and induction of apoptosis in replicating cells seemed to be related to an increase in cyclin d3 flanked by a decrease in cdk6 when ht concentration was 100 μm, whereas it was linked to an increase in p21 and p27 mrna and protein levels when ht was used at a concentration of 75 μm. as suggested by the authors, these observations may be explained in the light of cyclin d3 - dependent cdk6 - mediated phosphorylation of prb, which in turn causes the release of e2f transcription factor and g1 / s transition as well as dna synthesis. intriguingly, both p21 and p27 are able to inhibit cdk6 - mediated prb phosphorylation and accelerate hl - 60 differentiation. chronic myelogenous leukemia ( also known as chronic myeloid leukemia ) is a myeloproliferative neoplastic disease characterized by the chromosomal translocation t ( 9; 22 ) ( q34; q11. 2 ), resulting in the presence of the philadelphia chromosome. the mentioned translocation produces the bcr - abl1 fusion oncogene, encoding for a constitutively active tyrosine kinase, making leukemia cells sensitive to tyrosine kinase inhibition, with very good 5 - year survival rates ( 90 % ). incubation of chronic myelogenous leukemia cell line k562 for 4 days with 200 μg / ml ( ≈370 μm ) and 400 μg / ml ( ≈740 μm ) ole reduced cell density and viability. after 48 h treatment with 200 μg / ml ole, a significant activation of caspase - 1 was measured. also, 200 μg / ml ole caused a reduction in prdx - 1 protein level after 8 h of treatment, which was maintained after 24 h. treatment of k562 cells with concentrations of ht up to 1000 μm produced a dose - dependent reduction in cell viability ( ec50 = 147 μm ) with concomitant increase in caspase 3 / 7 activity. acute monocytic leukemia is the expression formerly utilized to indicate a neoplastic lesion arising from the loss of normal maturation along the monocytic lineage, and is now included in the larger category labeled as acute myeloid leukemia ( that is the most frequent leukemia among adults ). thp - 1 is probably the most known acute monocytic leukemia cell line. among all ht doses tested ( 1 – 40 μm ), only 20 μm affected viability of thp - 1 cells after 72 h. instead, in u937 cells ( a human acute myeloid leukemia cell line of pro - monocytic origin ), 75 μm and 200 μm ht increased cell death and apoptosis. t - cell acute lymphoblastic leukemia ( t - all ) represents the consequence of the loss of proper regulation of t - cell development, resulting in the accumulation of immature progenitors. with conventional therapies, survival is lower among adult patients vs. pediatric subjects, mainly because of treatment - associated toxicity and higher relapse rates in adults. treatment of t - all cell line ccrf - cem with ht concentrations up to 1000 μm produced a dose - dependent reduction in cell viability ( ec50 = 338 μm ), flanked by the increase in caspase 3 / 7 activity.