Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D (SDHx) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

• MeSH
• feochromocytom farmakoterapie   enzymologie   genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• kyselina jantarová metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• paragangliom farmakoterapie   enzymologie   genetika   metabolismus   MeSH
• podjednotky proteinů genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• sukcinátdehydrogenasa nedostatek   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

PURPOSE: Pheochromocytomas and paragangliomas (PCPG) are usually benign neuroendocrine tumors. However, PCPGs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions. SDHB-mutated PCPGs exhibit dysregulation in oxygen metabolic pathways, including pseudohypoxia and formation of reactive oxygen species, suggesting that targeting the redox balance pathway could be a potential therapeutic approach. EXPERIMENTAL DESIGN: We studied the genetic alterations of cluster I PCPGs compared with cluster II PCPGs, which usually present as benign tumors. By targeting the signature molecular pathway, we investigated the therapeutic effect of ascorbic acid on PCPGs using in vitro and in vivo models. RESULTS: By investigating PCPG cells with low SDHB levels, we show that pseudohypoxia resulted in elevated expression of iron transport proteins, including transferrin (TF), transferrin receptor 2 (TFR2), and the divalent metal transporter 1 (SLC11A2; DMT1), leading to iron accumulation. This iron overload contributed to elevated oxidative stress. Ascorbic acid at pharmacologic concentrations disrupted redox homeostasis, inducing DNA oxidative damage and cell apoptosis in PCPG cells with low SDHB levels. Moreover, through a preclinical animal model with PCPG allografts, we demonstrated that pharmacologic ascorbic acid suppressed SDHB-low metastatic lesions and prolonged overall survival. CONCLUSIONS: The data here demonstrate that targeting redox homeostasis as a cancer vulnerability with pharmacologic ascorbic acid is a promising therapeutic strategy for SDHB-mutated PCPGs.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• feochromocytom farmakoterapie   genetika   patologie   MeSH
• genový knockdown MeSH
• kyselina askorbová farmakologie   terapeutické užití   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši MeSH
• nádorové buněčné linie transplantace   MeSH
• oxidační stres účinky léků   MeSH
• paragangliom MeSH
• poškození DNA účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• sukcinátdehydrogenasa nedostatek   genetika   MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Feochromocytom patří mezi nádory s velmi nízkou incidencí a vyskytuje se sporadicky nebo v rámci MEN (mnohočetné endokrinní neoplazie). Uvádíme případ pacientky, v době diagnózy ve věku 55 let, se sporadickým výskytem feochromocytomu, zachyceném ve fázi mnohočetné disseminace do dutiny břišní se zvýšenou expresí adrenalinu, noradrenalinu a dopaminu. Pacientka byla léčena kombinací TACE, systémové léčby hormonálním přípravkem lanreotid a systémovou cílenou léčbou s velmi dobrým účinkem. Zatím pacientka žije pět let od diagnózy disseminace a 18 let od primomanifestace choroby v dobré kvalitě života. Případ dokumentuje dobrý účinek zvolené hormonální i protinádorové léčby.

Pheochromocytomas are rare tumors. Bilateral adrenal medullary pheochromocytomas are components of MEN- Ila and MEN Ilb (multiple endocrine neoplasia). Patient 55 years old with inoperable pheochromocytoma, with liver and abdomen cavity metastases in the time of diagnosis had high levels of adrenalin, noradrenalin and dopamin. Patient was treated by TACE, lanreotide and target therapy. The patient lives 5 years after the diagnosis of disease dissemination and 18 years after the first manifestation, with very good effect and quality of life. The case demonstrates the good effect of hormonal and anti-cancer treatment.

• MeSH
• antitumorózní látky hormonální aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chemoembolizace metody   trendy   MeSH
• cílená molekulární terapie * metody   trendy   MeSH
• cyklické peptidy terapeutické užití   MeSH
• feochromocytom * diagnóza   farmakoterapie   chirurgie   MeSH
• kombinovaná terapie metody   trendy   MeSH
• lidé MeSH
• mezenterium chirurgie   MeSH
• mnohočetné endokrinní neoplazie diagnóza   etiologie   terapie   MeSH
• senioři MeSH
• somatostatin analogy a deriváty   terapeutické užití   MeSH
• statistika jako téma MeSH
• sunitinib * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

OBJECTIVE: Paroxysmal hypertension or pseudopheochromocytoma is quite a common problem in clinical practice. The optimal treatment for this condition has not been established. This study sought to investigate whether sertraline (a selective serotonin reuptake inhibitor) reduces the symptoms. METHODS: We enrolled 64 patients referred to our department between April 2008 and October 2014 for symptomatic paroxysmal hypertension. Patients received sertraline, 50 mg once daily, in addition to their current medication. The effect of the treatment was assessed during their next clinical visit at least 3 months later. RESULTS: Of the 64 patients, 57 (89%) also had sustained arterial hypertension. Mean office baseline blood pressure (BP) was 147.6/83.8 mmHg and patients used a mean of 3.1 antihypertensive drugs. Five patients did not start using sertraline and three were lost to follow-up. Of the 56 patients who started using sertraline and who came for check up, clinical improvement was observed in 42 (75%) patients - symptoms of paroxysmal hypertension fully subsided in 28 (50%) and were partially reduced in 14 (25%) . Side effects or intolerance leading to discontinuation of treatment occurred in 7 patients (12.5%). Mean office BP in patients using sertraline decreased by 12.8/7.4 mmHg (P<0.001 for both). CONCLUSIONS: Sertraline effectively removed or reduced symptoms of paroxysmal hypertension in the majority of patients who used this treatment.

• MeSH
• antihypertenziva aplikace a dávkování   MeSH
• feochromocytom farmakoterapie   MeSH
• hypertenze farmakoterapie   MeSH
• lidé MeSH
• retrospektivní studie MeSH
• rozvrh dávkování léků MeSH
• selektivní inhibitory zpětného vychytávání serotoninu aplikace a dávkování   MeSH
• senioři MeSH
• sertralin aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Sekundární arteriální hypertenze má určitou, v některých případech léčitelnou, příčinu. Na sekundární hypertenzi bychom měli myslet u mladých hypertoniků, u pacientů s rezistentní arteriální hypertenzí a při přítomnosti typických znaků pro sekundární hypertenzi. Při včasné diagnóze a správné léčbě může dojít k úplnému uzdravení pacienta.

Some causes of secondary hypertension are treatable. Hypertensive young adults, patients with resistant hypertension and patientswith specific secondary hypertension signs must be examined. An early diagnosis and treatment can lead to a complete recovery.

• MeSH
• Cushingův syndrom diagnóza   farmakoterapie   komplikace   MeSH
• feochromocytom diagnóza   farmakoterapie   komplikace   MeSH
• hypertenze * diagnóza   epidemiologie   klasifikace   MeSH
• hypokalemie diagnóza   etiologie   farmakoterapie   MeSH
• koarktace aorty diagnóza   farmakoterapie   komplikace   MeSH
• lidé MeSH
• obstrukce renální arterie diagnóza   farmakoterapie   komplikace   MeSH
• renální hypertenze diagnóza   farmakoterapie   komplikace   MeSH
• rodinní lékaři * MeSH
• směrnice pro lékařskou praxi jako téma * MeSH
• spironolakton terapeutické užití   MeSH
• statistika jako téma MeSH
• syndromy spánkové apnoe diagnóza   klasifikace   komplikace   MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• apoptóza genetika   MeSH
• biologické modely MeSH
• buněčný cyklus genetika   MeSH
• chemorezistence genetika   MeSH
• cílená molekulární terapie MeSH
• feochromocytom farmakoterapie   genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mitochondrie metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši MeSH
• NAD metabolismus   MeSH
• nádorové buněčné linie MeSH
• oprava DNA * MeSH
• paragangliom farmakoterapie   genetika   metabolismus   patologie   MeSH
• PARP inhibitory farmakologie   terapeutické užití   MeSH
• poly(ADP-ribosa)-polymerasy metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• sukcinátdehydrogenasa genetika   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• buňky - růstové procesy účinky léků   MeSH
• endotelin-1 genetika   metabolismus   MeSH
• erythropoetin genetika   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• feochromocytom farmakoterapie   patologie   MeSH
• fosfoglycerátkinasa genetika   metabolismus   MeSH
• hypoxie farmakoterapie   patologie   MeSH
• idarubicin terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory nadledvin farmakoterapie   patologie   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vazba proteinů MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

• MeSH
• antitumorózní látky farmakologie   MeSH
• benzodioxoly aplikace a dávkování   farmakologie   MeSH
• buňky PC12 MeSH
• DNA-topoisomerasy I metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• feochromocytom farmakoterapie   enzymologie   patologie   MeSH
• hypoxie buňky MeSH
• inhibitory topoisomerasy I aplikace a dávkování   farmakologie   MeSH
• isochinoliny aplikace a dávkování   farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádory jater farmakoterapie   enzymologie   sekundární   MeSH
• nádory nadledvin farmakoterapie   enzymologie   patologie   MeSH
• nádory plic farmakoterapie   enzymologie   sekundární   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• synergismus léků MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Intramural MeSH

Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.

• MeSH
• aktiny metabolismus   MeSH
• antigeny CD34 metabolismus   MeSH
• časové faktory MeSH
• chromogranin A metabolismus   MeSH
• feochromocytom farmakoterapie   metabolismus   patologie   MeSH
• hladké svalstvo chemie   MeSH
• homologní transplantace MeSH
• imunohistochemie MeSH
• isotretinoin aplikace a dávkování   farmakologie   MeSH
• lovastatin aplikace a dávkování   farmakologie   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory nadledvin farmakoterapie   metabolismus   patologie   MeSH
• nádory plic metabolismus   prevence a kontrola   sekundární   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• tumor burden účinky léků   MeSH
• tyrosin-3-monooxygenasa metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Drug repurposing or repositioning is an important part of drug discovery that has been growing in the last few years for the development of therapeutic options in oncology. We applied this paradigm in a screening of a library of about 3,800 compounds (including FDA-approved drugs and pharmacologically active compounds) employing a model of metastatic pheochromocytoma, the most common tumor of the adrenal medulla in children and adults. The collection of approved drugs was screened in quantitative mode, testing the compounds in compound-titration series (dose-response curves). Analysis of the dose-response screening data facilitated the selection of 50 molecules with potential bioactivity in pheochromocytoma cells. These drugs were classified based on molecular/cellular targets and signaling pathways affected, and selected drugs were further validated in a proliferation assay and by flow cytometric cell death analysis. Using meta-analysis information from molecular targets of the top drugs identified by our screening with gene expression data from human and murine microarrays, we identified potential drugs to be used as single drugs or in combination. An example of a combination with a synergistic effect is presented. Our study exemplifies a promising model to identify potential drugs from a group of clinically approved compounds that can more rapidly be implemented into clinical trials in patients with metastatic pheochromocytoma or paraganglioma.

• MeSH
• antitumorózní látky farmakologie   MeSH
• dospělí MeSH
• feochromocytom farmakoterapie   genetika   sekundární   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• myši MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory nadledvin farmakoterapie   genetika   patologie   MeSH
• objevování léků * MeSH
• paragangliom farmakoterapie   genetika   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• přehodnocení terapeutických indikací léčivého přípravku * MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• rychlé screeningové testy * MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• stanovení celkové genové exprese MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Intramural MeSH