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1.
Biomed Chromatogr ; 34(3): e4776, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31826297

RESUMO

Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14-20 µg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) was developed. Through deproteination and liquid-liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC-EI-MS yielded retention times of 8.2 and 8.7 min, for mitotane and the IS, respectively, with a total run time of 12 min. Selectivity and intra-/inter-batch accuracy and precision analyses provided a lower limit of quantification of 0.25 µg/mL, and a calibration curve between 0.25 and 40 µg/mL had good linearity (coefficient of determination = 0.992). The matrix effect factor and percent recovery of the method had good precision. Additionally, long-term sample stability was observed below 4°C. In a clinical setting, mitotane levels in plasma from an adrenal cortical carcinoma patient were within calibration range. Therefore, this simplified method can be applied to routine therapeutic drug monitoring of mitotane, which may contribute to improved treatment of adrenal cortical carcinoma.


Assuntos
Antineoplásicos Hormonais/sangue , Monitoramento de Medicamentos/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Mitotano/sangue , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/uso terapêutico , Humanos , Limite de Detecção , Modelos Lineares , Mitotano/química , Mitotano/farmacocinética , Mitotano/uso terapêutico , Reprodutibilidade dos Testes
2.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513709

RESUMO

CONTEXT: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. OBJECTIVE: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. DESIGN, SETTING, AND INTERVENTION: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. RESULTS: Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. CONCLUSIONS: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Modelos Animais de Doenças , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/imunologia , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Proliferação de Células , Feminino , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Morte Celular Programada 1/imunologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Surgery ; 167(1): 233-240, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561992

RESUMO

INTRODUCTION: Adrenocortical carcinoma is an aggressive cancer with a poor prognosis. Long noncoding RNAs are differentially expressed in cancer patients and contribute to cellular homeostasis, survival, and metastasis. We hypothesize that our novel C-terminal Hsp90 inhibitor KU758 can effectively target adrenocortical carcinoma cells and favorably alter long noncoding RNA expression. METHODS: Cell viability after KU758 treatment was measured in the adrenocortical carcinoma cell lines SW13, RL251, and NCI-H295R by MTS assay. Cellular mobility and metastatic potential after Hsp90 inhibition was measured through migration, invasion, and aggregate formation assays. ß-catenin activity in NCI-H295R cells was determined by immunofluorescence and polymerase chain reaction. Long noncoding RNA expression was determined by polymerase chain reaction array after Hsp90 inhibition. RESULTS: KU758 is selective for adrenocortical carcinoma cells with IC50 values of 0.6 to 2.4 µM. KU758 treatment can effectively reduce migration, invasion, and aggregate formation in NCI-H295R and SW13 cells. ß-catenin activity is decreased after treatment with KU758. Treatment with KU758 is associated with overall statistically significant upregulation of long noncoding RNA expression, including the tumor suppressor GAS5, which is implicated in the ß-catenin and mammalian target of rapamycin pathways in adrenocortical carcinoma. CONCLUSION: The novel C-terminal Hsp90 inhibitor KU758 is effective in the treatment of adrenocortical carcinoma cells and can significantly alter long noncoding RNA expression for tumor suppression.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Concentração Inibidora 50 , Regulação para Cima/efeitos dos fármacos
4.
Eur J Endocrinol ; 181(6): 681-689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639772

RESUMO

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro. Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy. Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety. Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria. Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteínas Supressoras de Tumor/metabolismo
5.
Drug Des Devel Ther ; 13: 2787-2798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496655

RESUMO

Objective: Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods: In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results: The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion: Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Tapsigargina/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Thapsia/química , Tapsigargina/química , Células Tumorais Cultivadas
6.
Endocrinology ; 160(11): 2620-2629, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31397841

RESUMO

Abiraterone acetate (AbiAc) inhibits tumor growth when administered to immunodeficient mice engrafted with the in vitro cell model of human adrenocortical carcinoma (ACC). Here, we developed and validated a zebrafish model engrafted with cortisol-secreting ACC cells to study the effects of AbiAc on tumor growth. The experimental conditions for AbiAc absorption in AB zebrafish embryos including embryo number, AbiAc concentration, and absorption time curve by liquid chromatography-tandem mass spectrometry were set up. The AbiAc effect on steroid production in AB zebrafish embryos was measured as well. ACC cells (the NCI-H295R cell line, the primary cell ACC29, and the negative control cell SW13) were treated with drug-induced liver injury fluorescent dye, and ∼240 cells per 4 nL was injected in the subperidermal space of the yolk sac of AB zebrafish embryos (n = 80 ± 10). The cell area was measured with Noldus DanioScopeTM software. AbiAc absorption in AB zebrafish embryos was stage dependent. Abiraterone (Abi) concentration decreased, whereas its main metabolite, Δ4A, increased. Accordingly, we demonstrated that zebrafish expressed mRNA encoding the enzyme 3ß-hydroxysteroid dehydrogenase, which converts Abi in Δ4A. Furthermore, ABiAc reduced cortisol production and increased progesterone in zebrafish embryos. Three days after cell injection, the cortisol-secreting ACC cell area in solvent-treated embryos was significantly higher than that in 1 µM AbiAC‒treated embryos, whereas no AbiAc effect was observed in SW13 cells, which lack the Abi target enzyme CYP17A1.Zebrafish embryos xenografted with ACC tumor cells could be a useful, fast, and reproducible experimental model to preclinically test the activity of new drugs in human ACC.


Assuntos
Acetato de Abiraterona/uso terapêutico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
7.
Invest New Drugs ; 37(4): 755-762, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31172443

RESUMO

Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Gossipol/análogos & derivados , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Feminino , Gossipol/efeitos adversos , Gossipol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2 , Critérios de Avaliação de Resposta em Tumores Sólidos
8.
J Steroid Biochem Mol Biol ; 192: 105413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202858

RESUMO

In steroid-producing cells, cholesterol transport from the outer to the inner mitochondrial membrane is the first and rate-limiting step for the synthesis of all steroid hormones. Cholesterol can be transported into mitochondria by specific mitochondrial protein carriers like the steroidogenic acute regulatory protein (StAR). StAR is phosphorylated by mitochondrial ERK in a cAMP-dependent transduction pathway to achieve maximal steroid production. Mitochondria are highly dynamic organelles that undergo replication, mitophagy and morphology changes, all processes allowed by mitochondrial fusion and fission, known as mitochondrial dynamics. Mitofusin (Mfn) 1 and 2 are GTPases involved in the regulation of fusion, while dynamin-related protein 1 (Drp1) is the major regulator of mitochondrial fission. Despite the role of mitochondrial dynamics in neurological and endocrine disorders, little is known about fusion/fission in steroidogenic tissues. In this context, the present work aimed to study the role of angiotensin II (Ang II) in protein subcellular compartmentalization, mitochondrial dynamics and the involvement of this process in the regulation of aldosterone synthesis. We demonstrate here that Ang II stimulation promoted the recruitment and activation of PKCε, ERK and its upstream kinase MEK to the mitochondria, all of them essential for steroid synthesis. Moreover, Ang II prompted a shift from punctate to tubular/elongated (fusion) mitochondrial shape, in line with the observation of hormone-dependent upregulation of Mfn2 levels. Concomitantly, mitochondrial Drp1 was diminished, driving mitochondria toward fusion. Moreover, Mfn2 expression is required for StAR, ERK and MEK mitochondrial localization and ultimately for aldosterone synthesis. Collectively, this study provides fresh insights into the importance of hormonal regulation in mitochondrial dynamics as a novel mechanism involved in aldosterone production.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Carcinoma Adrenocortical/metabolismo , Angiotensina II/farmacologia , Colesterol/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Quinases/metabolismo , Vasoconstritores/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Transporte Biológico , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação , Células Tumorais Cultivadas
9.
J Drugs Dermatol ; 18(5): 468-469, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141856

RESUMO

Sorafenib is an oral multikinase inhibitor approved by the United States Food and Drug Administration for the treatment of advanced hepatocellular and renal cell carcinoma. Cases of sorafenib-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported in the literature. DRESS syndrome is a potentially fatal, drug-induced hypersensitivity reaction that occurs 2-8 weeks after drug exposure. DRESS syndrome presents with generalized morbilliform eruption, facial edema, eosinophilia, and end-organ damage. We present the first reported case of sorafenib toxicity mimicking DRESS syndrome in a patient with metastatic adrenocortical carcinoma presenting with fever, morbilliform rash, and transaminitis in the absence of eosinophilia three days following initiation of sorafenib therapy. It is critical that clinicians are equipped to accurately diagnose DRESS syndrome due to its high mortality rate and the morbidity associated with prolonged steroid therapy. J Drugs Dermatol. 2019;18(5):468-469.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Sorafenibe/toxicidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/secundário , Diagnóstico Diferencial , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica
10.
Eur J Endocrinol ; 180(6): 387-396, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991359

RESUMO

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mitotano/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
11.
Int J Oncol ; 54(6): 2149-2156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942448

RESUMO

Mitotane (also termed o,p'­DDD) is the most effective therapy for advanced adrenocortical carcinoma (ACC). Mitotane­induced dyslipidemia is treated with statins. Mitotane and statins are known to exert anti­proliferative effects in vitro; however, the effects of statins have never been directly evaluated in patients with ACC and ACC cells, at least to the best of our knowledge. Thus, in this study, we aimed to examine the effects of the rosuvastatin on ACC cells. It has been shown that the combined use of mitotane and statins significantly increases the tumor control rate in patients with ACC; however, it would be of interest to elucidate the molecular mechanisms involved in this potentiation. In this study, we examined the effects of mitotane, rosuvastatin and their combination in NCI­H295R human ACC cells using proliferation assays, gene expression analyses and free intracellular cholesterol measurements. The results revealed that mitotane dose­dependently reduced cell viability, induced apoptosis and increased intracellular free cholesterol levels, considered as one of the key features of mitotane action, while rosuvastatin alone reduced cell viability and increased apoptosis at high concentrations. We also demonstrated that rosuvastatin potentiated the effects of mitotane by reducing cell viability, inducing apoptosis, increasing intracellular free cholesterol levels, and by decreasing the expression of 3­hydroxy­3­methylglutaryl­CoA reductase (HMGCR) and ATP binding cassette subfamily a member 1 (ABCA1), genes involved in cholesterol metabolism, and inhibiting steroidogenesis. Collectively, potentiating the effects of mitotane with the use of rosuvastatin may provide novel therapeutic strategies for ACC, given that the combination of these drugs, pending clinical validation, may lead to the better management of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Mitotano/farmacologia , Rosuvastatina Cálcica/farmacologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Mitotano/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico
12.
Endocrine ; 64(3): 673-684, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30838516

RESUMO

PURPOSE: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. METHODS: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. RESULTS: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. CONCLUSIONS: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Imidazóis/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
J Chemother ; 31(2): 105-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831058

RESUMO

A 43-years old woman was diagnosed an adrenocortical carcinoma (AC) that was excised, whereas two lung metastases were un-operable. Mitotane 6 g/day was started as standard therapy but it was responsible for severe central nervous system (CNS) and gastrointestinal toxicities associated with a 10 kg body weight loss. A therapeutic drug monitoring (TDM) protocol demonstrated that mitotane plasma concentrations (>30 mg/L) exceeded the therapeutic range (14-20 mg/L) and increased even when drug daily dose was reduced by 50%. The increase in drug plasma concentrations was probably due to body slimming. Under continuous TDM control, a reduced mitotane dose (1.5 g/day) was definitively administered and it proved to be tolerable and effective. Indeed, lung metastases were excised and two years later there was no evidence of other neoplastic lesions. In conclusion, the adoption of therapeutic mitotane monitoring allowed the treatment of an AC patient with a reduced, tolerable and effective dose.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Monitoramento de Medicamentos/normas , Mitotano/administração & dosagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Prognóstico
14.
Exp Clin Endocrinol Diabetes ; 127(2-03): 109-116, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469158

RESUMO

Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Antibióticos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Humanos
15.
J Cell Biochem ; 120(1): 894-906, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256438

RESUMO

Unraveling molecular mechanisms that regulate tumor development and proliferation is of the utmost importance in the quest to decrease the high mortality rate of adrenocortical carcinomas (ACC). Our aim was to evaluate the role of two of the mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-regulated protein kinases [ERKs 1/2] and p38) in the adrenocortical tumorigenesis, as well as the therapeutic potential of MAPK/ERK inhibition. ERKs 1/2 and p38 activation were evaluated in incidentalomas (INC; n = 10), benign Cushing's syndrome (BCS; n = 12), malignant Cushing's syndrome (MCS; n = 6) and normal adrenal glands (NAG; 8). ACC cell line (H295R) was used to evaluate the ability of PD184352 (0.1, 1, and 10 µM), a specific MEK-MAPK-ERK pathway inhibitor, to modulate cell proliferation, viability, metabolism, and steroidogenesis. ERKs 1/2 activation was significantly higher in MCS (2.83 ± 0.17) compared with NAG (1.00 ± 0.19 "arbitrary units"), INC (1.20 ± 0.13) and BCS (2.09 ± 0.09). Phospho-p38 expression was absent in all the MCS analyzed. MAPK/ERK kinase (MEK) inhibition with PD184352 significantly decreased proliferation as well as steroidogenesis and also increased the redox state of the H295R cells. This data suggests that MEK-MAPK-ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Benzamidas/farmacologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Minerva Endocrinol ; 44(1): 70-81, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29808641

RESUMO

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. It has undergone in-depth clinical and laboratory investigations, with the help of the most important research groups all over the world. Nonetheless the cure for this kind of neoplasia is not right around the corner, given its complexity and multi-faceted feature, that lead researchers to think at "one person one ACC." Currently total resection is the most concrete option for ACC patients, whenever possible. Mitotane remains the main drug for primary or adjuvant therapy, but gives partial and unsatisfactory therapeutic results, especially in metastatic ACC. This prompted the researchers to find other ways to fight against this malignancy: targeted therapy seems the most promising answer, as it is based on biomolecular and genetic cancer signature. Numerous specific targets were explored for the treatment of ACC, such as those involving angiogenesis, steroidogenesis, Wnt/ß-catenin pathway and many others key factors. Even if large efforts have been made, no effective target therapy entered in the clinical use. This data should not be considered only as detrimental, rather it should propel scientific research to invest more resources into the therapeutic exploration of ACC and in particular on the most promising strategy, the targeted therapy.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma/terapia , Terapia de Alvo Molecular/métodos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Humanos
17.
Mol Cell Endocrinol ; 480: 36-41, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30315857

RESUMO

90 kDa heat shock proteins (Hsp90) act as protein chaperones and play a role in modulating endoplasmic reticulum (ER) stress. Hsp90 inhibitors are under clinical investigation as cancer treatment. Mitotane therapy of adrenocortical carcinoma (ACC) has been shown to act through lipid-induced ER-stress. To explore the potential of Hsp90 inhibitors in ACC as a single agent and in combination with mitotane, we analyzed two independent gene expression data sets of adrenal tumors in silico and treated the ACC cell line model NCI-H295 with Hsp90 inhibitors BIIB021 (B) and CCT18159 (C) alone and in combination with mitotane. ER-stress markers were monitored by immunoblotting. Drug synergism was quantified using the median effect model with cell viability as read-out. Cytosolic Hsp90 isoforms AA1 and AB1 were significantly overexpressed in ACC. Viability of H295 cells was impaired by B and C as single agents with an EC50 of 5.7 × 10-6M and 12.1 × 10-6M. B but not C dose-dependently increased XBP1 splicing and CHOP expression indicative of ER-stress activation. ER-stress marker expression was enhanced by co-incubation of B with 10  µM but not 5  µM mitotane. Maximal CHOP expression was induced by 25 µM mitotane alone with no additional effect of B. Combination indices (CI) of B and C with mitotane ranged from 0.64 to 1.38 and 0.68 to 1.30, respectively where CI values < 0.5 support clinically-relevant drug synergism. In conclusion, Hsp90 paralogs are differentially expressed in ACC and B but not C activates ER-stress in ACC cells. No meaningful drug synergism of Hsp90 inhibitors with mitotane was observed.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Mitotano/uso terapêutico , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Linhagem Celular , Simulação por Computador , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Humanos , Mitotano/farmacologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Endocrine ; 63(3): 592-601, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30367443

RESUMO

PURPOSE: The management of patients with adrenocortical carcinoma (ACC) is challenging. As mitotane and chemotherapy show limited efficacy, there is an urgent need to develop therapeutic approaches. The aim of this study was to investigate the antitumor activity of progesterone and explore the molecular mechanisms underlying its cytotoxic effects in the NCI-H295R cell line and primary cell cultures derived from ACC patients. METHODS: Cell viability, cell cycle, and apoptosis were analyzed in untreated and progesterone-treated ACC cells. The ability of progesterone to affect the Wnt/ß-catenin pathway in NCI-H295R cells was investigated by immunofluorescence. Progesterone and mitotane combination experiments were also performed to evaluate their interaction on NCI-H295R cell viability. RESULTS: We demonstrated that progesterone exerted a concentration-dependent inhibition of ACC cell viability. Apoptosis was the main mechanism, as demonstrated by a significant increase of apoptosis and cleaved-Caspase-3 levels. Reduction of ß-catenin nuclear translocation may contribute to the progesterone cytotoxic effect. The progesterone antineoplastic activity was synergically increased when mitotane was added to the cell culture medium. CONCLUSIONS: Our results show that progesterone has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of progesterone with mitotane provides the rationale for testing this combination in a clinical study.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Proteínas de Membrana/metabolismo , Mitotano/uso terapêutico , Cultura Primária de Células , Progesterona/farmacologia , Progestinas/farmacologia , Receptores de Progesterona/metabolismo , beta Catenina/metabolismo
19.
Exp Clin Endocrinol Diabetes ; 127(9): 578-584, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30428495

RESUMO

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often temporary and salvage treatments are warranted. METHODS: Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tumours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radiologists, and overall survival (OS). RESULTS: Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was administered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and progressive disease (n=25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontinued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints). CONCLUSION: Thalidomide was overall well tolerated but resulted in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Sistema de Registros , Talidomida/administração & dosagem , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
20.
Nihon Hinyokika Gakkai Zasshi ; 110(1): 12-17, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31956212

RESUMO

A 77-year-old man with a complaint of impaired consciousness was brought to our emergency department. The patient was referred to our department because of a huge retroperitoneal tumor and multiple pulmonary nodules detected on computed tomography. Owning to an abnormally high level of dehydroepiandrosterone sulfate, right adrenal cancer was suspected. Pathological examination of the retroperitoneal tumor by echo-guided pericutaneous biopsy revealed an adrenocortical carcinoma. Under the diagnosis of stage IV adrenocortical carcinoma, mitotane therapy was started in May 2013. We adjusted the mitotane dose on the basis of the clinical evidence and the adrenocorticotropic hormone and cortisol levels.The tumors had increased in size after 2 months of the mitotane therapy. However, 2 months later, the tumor had significantly decreased in size. The treatment was continued for 53 months until he could no longer take medications orally, because of his advanced age, worse condition, and disuse syndrome.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Mitotano/administração & dosagem , Idoso , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Resultado do Tratamento
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