Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation.
Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-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.
Cerquetti
Lidia
L
II Faculty of Medicine, Sapienza University of Rome, Endocrinology Sant'Andrea Hospital, Via di Grottarossa 1035, Rome 00189, Italy.
Sampaoli
Camilla
C
Amendola
Donatella
D
Bucci
Barbara
B
Misiti
Silvia
S
Raza
Giorgio
G
De Paula
Ugo
U
Marchese
Rodolfo
R
Brunetti
Ercole
E
Toscano
Vincenzo
V
Stigliano
Antonio
A
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018268:Adrenocortical Carcinoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D019926:Cyclin B / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000502:physiology; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008939:Mitotane / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; D019926:Cyclin B; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011687:Purines; D011838:Radiation-Sensitizing Agents; D008939:Mitotane; D018844:Cyclin-Dependent Kinases; D045643:DNA Repair Enzymes