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M Muratori, I Nicoletti, G B Vannelli, M Luconi, E Macorsini, M Serio, G Forti, and M Maggi

Abstract

We report evidence indicating that the isoflavone genistein induces a dose-dependent antiproliferative effect in the human uterine adenocarcinoma cell lines HEC-1A, HEC-1B, AN3 CA and RL95-2. Cell growth inhibition resulted from a partial G2/M block and from the appearance of a hypodiploid DNA peak (reduction in nuclear DNA content), suggestive of apoptosis. In HEC-1A cells, we found that both cell cycle impairment and the appearance of a hypodiploid DNA peak were time-dependent, triggered by similar concentrations of the isoflavone and not affected by the presence of serum in the culture medium. However, while the genistein-induced cell cycle'arrest was fully reversible, the appearance of the hypodiploid DNA peak was not. To verify whether the appearance of a hypodiploid DNA peak corresponded to apoptosis, we used in situ end labelling (ISEL) and transmission electron microscopy (TEM) in HEC-1A cells. We found that a 48-h treatment with genistein induced ISEL positivity only in a minority of cells, while at 72 h the majority of cells were labelled. At this time TEM showed the typical ultrastructural features of apoptosis, including apoptotic bodies.

Because genistein inhibited tyrosine kinase (TK) and topoisomerase (Topo) II activity in HEC-1A cells and its effects were mimicked by structurally unrelated TK and Topo II inhibitors, we speculate that interactions with TK and Topo II are relevant for the antiproliferative effect of genistein. Conversely, the antiproliferative effect of genistein seems to be independent of its oestrogenic activity. Our data indicate that genistein inhibits the growth of uterine adenocarcinoma cell lines by inducing cell cycle arrest and apoptosis.

Endocrine-Related Cancer (1997) 4 203-218

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S G Creemers, R A Feelders, N Valdes, C L Ronchi, M Volante, B M van Hemel, M Luconi, M H T Ettaieb, M Mannelli, M D Chiara, M Fassnacht, M Papotti, M N Kerstens, G Nesi, H R Haak, F J van Kemenade, and L J Hofland

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224–6.343; OR 1.467 95% CI 1.202–1.792, respectively; Hosmer–Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930–0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866–0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285–2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.