despite being considered as a t - all cell line, jurkat cells are immunophenotypically different from t - all cells; thus, results obtained in this cell model retain modest reliability. a study performed using an ht - rich natural extract of the olive pulp as a source of ht demonstrated a dose - dependent reduction in cell viability and induction of apoptosis, together with ros accumulation. as the literature analysis in section 2 and section 3 corroborates, methodological standar diz ation for the study of the effects of natural products may reveal to be challenging, mainly as a consequence of the combination of the multiplicity of molecular patterns triggered and effects elicited by these substances, together with the intrinsic variability of the biological systems ( cancer cells and interaction with the surrounding tissue cells ) of interest. the dissertation above seems to validate the use of ole and ht as cytotoxic agents, with the chance of a further employment of both compounds as microenvironment modulators ( ole - and ht - dependent effects on cancer cell viability and behavior are summarized in figure 2 ). however, before extrapolating any conclusion, the reported data should be interpreted and discussed in the light of factors determining the feasibility of such a purpose. in the next paragraphs, we discuss the role of ole and ht absorption, bioavailability and toxicity to non - cancer cells, ole and ht interaction with chemotherap y drugs, ole - and ht - mediated repercussions on drug metabolism, and ole and ht antioxidant activity in the context of chemotherap y - induced oxidative stress as determinants of the net ole and ht activity on cancer insurgence and growth in humans. factors influencing ole and ht effects in human cancers are reported in figure 2. information about ole and ht absorption through the digestive tract and bioavailability is limited, and often arises from a combination of experimental proofs obtained from humans and animal models. after ingestion, ole remains mostly stable in the acid gastric environment, although non - enzymatic hydrolysis may account for an increased amount of ht reaching the small intestine. ole is poorly absorbed through the small intestine ( mainly via diffusion ), as demonstrated in rats and humans, enters systemic circulation, undergoes sulphate and glucuronide conjugation and / or enzymatic conversion in ht, and is eliminated in urine mainly as a glyco n and glucuronide derivatives. in the large intestine, ole is metabolized by gut microbiota, producing ht. after ingestion, ht is more largely absorbed in the intestine by diffusion, is mainly metabolized into glucuronide and sulphate conjugates, and is excreted in urine mostly in its glucuronide conjugated form. for both ole and ht ( and their metabolites ), the maximum excretion rate is reached in 4 h in humans. all these aspects may represent a potential source of difficulties if the objective is achieving and maintaining pharmacologically relevant concentrations of ole and ht in plasma after ingestion. whenever performing a critical evaluation of ole and ht availability, data from animal models should be taken into account with caution, since it has been demonstrated that the rate of excretion of ht differs between humans and rats ( being more rapid in humans ). thus, only data related to ole and ht plasma concentrations in humans are listed in this section. in a group of volunteers, the efficacy of ole delivery was assayed for liquid and capsule preparations, each containing a lower ( 64 mg total olive phenols, with 51. 1 mg ole ) or a higher ( 96 mg total, with 76. 6 mg ole ) dose. the best performance was offered by higher dose liquid preparation, with a mean peak of plasma ole ± s. d. = 3. 55 ± 2. 27 ng / ml and a mean time to peak ± s. d. = 20 ± 12 min, whereas the worst ole peak plasma values were detected for the lower dose capsule preparation ( mean peak ± s. d. = 0. 52 ± 0. 24 ng / ml, mean time to peak ± s. d. = 40 ± 27 min ). in humans, the assumption of 5 mg ht added to extra virgin olive oil produced a plasma peak of 3. 79 ng / ml after 30 min, followed by a rapid decline in ht plasma concentration ( minimum reached value < 2 ng / ml after 240 min ). this result matched another report documenting that the consumption of ht - enriched biscuits ( containing 5. 25 mg ht ) determined the appearance of ht metabolites in the volunteers ’ plasma between 30 min and 1 h. a similar pharmacokinetic effect was reported in other experimental settings using olive - derived watery supplements as a source of ht. the ingestion of 40 ml of high ( 366 mg / kg ) - phenolic - compound - content olive oil led to a plasma ht concentration peak of ≈15 μm ( mean time to peak ± s. d. = 0. 91 ± 0. 84 h, mean estimated elimination half - life ± s. d. = 3. 00 ± 1. 46 h ), whereas the same amount of low - ( 2. 7 mg / kg ) and medium ( 164 mg / kg ) - phenolic - compound - content olive oil produced an ht peak of ≈5 μm or less. the assumption of 25 ml of extra virgin olive oil led to a maximum plasma concentration = 4. 4 ng / ml, ( time to peak = 0. 25 h ), and the ingestion of 25 ml of low - phenolic - content ( 10 mg / kg ), moderate - phenolic - content ( 133 mg / kg ), and high - phenolic - content ( 486 mg / kg ) olive oil produce a plasma ht peak of ≈5 nm, 25 nm, and 50 nm, respectively. on the basis of these pieces of data, it becomes evident that cytotoxicity and anti - cancer effects of ole and ht were recorded at concentrations largely exceeding those reachable with diet / olive oil consumption, and ole and ht pharmacokinetics does not match the requested treatment duration to exert an anti - proliferative effect. thus, it is difficult to imagine how ole and ht may be used as cancer - preventive / treating agents if the route of administration is ingestion. also, given that both phenols are extensively metabolized and rapidly excreted, the safety and efficacy of other routes of administration ( e. g., intravenous ) should be assessed in detail. 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, nonmalignant human bronchial epithelial beas - 2b cell line, normal colonic cell line ccd - 841con, human normal liver cell line ( hl - 7702 ), human normal prostate epithelial cells pwle2, human bile duct cell line hibepic, human fibroblasts wi - 38, normal skin fibroblast cell line ws1, human gn61 gingival fibroblasts, human lymphocytes, human pbmcs, and normal human fibroblasts. 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 and human normal prostate rwpe - 1 cells. the evaluation of ole and ht safety profile in cancer patients is still pending. some experimental proof has demonstrated that ole and ht may potentiate the effect of both routinely employed and new potential anti - cancer drugs. in human melanoma cell line a375, the combination of 250 μm ole with alkylating agent dacarbazine was more effective in reducing cell viability than dacarbazine alone. in female breast cancer patients undergoing neoadjuvant chemotherap y, orally administered 15 mg / kg ht determined a significant decrease in plasma levels of timp - 1 during treatment with epirubicin and cyclophosphamide. in an in vivo model of tumor xenograft ( tripl e negative mda - mb - 231 cell line ) in balb / c olahsd - foxn1 mice, peritoneally injected 50 mg / kg ole for 4 weeks exhibited a synergistic effect with doxorubicin on inhibition of tumor growth and induction of apoptosis.