title: RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization.
abstract: The anti-proliferative activity of mitotane (o,p'DDD) in adrenocortical cancer is mediated by its metabolites o,p'DDE and o,p'DDA. We previously demonstrated a functional link between ribonucleotide reductase M1(RRM1) expression and o,p'DDD activity, but the mechanism is unknown. In this study we assessed the impact of RRM1 on the bioavailability and cytotoxic activity of o,p'DDD, o,p'DDE and o,p'DDA in SW13 and H295R cells. In H295R cells, mitotane and its metabolites showed a similar cytotoxicity and RRM1 expression was not influenced by any drug. In SW13 cells, o,p'DDA only showed a cytotoxic activity and did not modify RRM1 expression, whereas the lack of sensitivity to o,p'DDE was associated to RRM1 gene up-modulation, as already demonstrated for o,p'DDD. RRM1 silencing in SW13 cells increased the intracellular transformation of mitotane into o,p'DDE and o,p'DDA. These data demonstrate that RRM1 gene interferes with mitotane metabolism in adrenocortical cancer cells, as a possible mechanisms of drug resistance.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Germano
authors.affiliation: Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.affiliation: Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.affiliation: Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: De Francia
authors.affiliation: Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy; IRCC, Institute for Cancer Research and Treatment, Candiolo, 10060 Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Migliore
authors.affiliation: Medical Oncology, University of Brescia, 25123 Brescia, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.affiliation: Department Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy. Electronic address: mauro.papotti@unito.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006801:Humans; D008939:Mitotane / Q000493:pharmacokinetics*; D012262:Ribonucleoside Diphosphate Reductase; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D025521:Tumor Suppressor Proteins; D008939:Mitotane; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase
keywords: Adrenocortical cancer; Cell lines; Metabolites; Mitotane; RRMI