TY - JOUR AB - Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11β-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10−5 M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability. AD - Endocrinology Sant'Andrea Hospital, II Faculty of Medicine, ‘Sapienza’ University of Rome, Rome 00189, Italy null AU - Cerquetti,Lidia AU - Sampaoli,Camilla AU - Amendola,Donatella AU - Bucci,Barbara AU - Misiti,Silvia AU - Raza,Giorgio AU - De Paula,Ugo AU - Marchese,Rodolfo AU - Brunetti,Ercole AU - Toscano,Vincenzo AU - Stigliano,Antonio DA - 2010/08/01 DO - 10.3892/ijo_00000698 EP - 501 IS - 2 JO - Int J Oncol PY - 2010 SN - 1019-6439 1791-2423 SP - 493 ST - Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation T2 - International Journal of Oncology TI - Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation UR - https://doi.org/10.3892/ijo_00000698 VL - 37 ER -