Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

Proscillaridin A inhibits hepatocellular carcinoma progression through inducing mitochondrial damage and autophagy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. At present, drug options for systemic treatment of HCC are very limited. There is an urgent need to develop additional effective drugs for HCC treatment. In the present study, we found that proscillaridin A (ProA), a cardiac glycoside, exerted a strong anticancer effect on multiple HCC cell lines. ProA significantly inhibited the cell proliferation, migration, and invasion of HCC cells. ProA also had a marked inhibitory effect on the progression of HCC in the MHCC97H xenograft nude mouse model. ProA-mediated suppression of HCC was closely related to cell apoptosis. ProA-treated HCC cells displayed significant mitochondrial damage and elevated reactive oxygen species production, resulting in profound cell apoptosis. Meanwhile, ProA also played a role in autophagy induction in HCC cells. Defects in autophagy partially relieved ProA's anticancer effect in HCC cells. Our findings demonstrate that ProA can effectively inhibit HCC progression and may serve as a potential therapeutic agent for HCC treatment.

Proscillaridin A slows the prostate cancer progression through triggering the activation of endoplasmic reticulum stress.

Prostate cancer (PCa) is the second commonly diagnosed malignancy in men over the world. Although androgen deprivation therapy for advanced PCa patients has significantly improved their survival, the majority of these patients eventually develop castration-resistant prostate cancer (CRPC). Proscillaridin A (Pro A), a cardiac glycoside that is clinically used to treat various heart failure diseases, has been reported to have anticancer activity in several cancers. However, whether Pro A exerts an inhibitory effect on PCa progression remains unknown. In this study, we determined possible antitumor effects of Pro A on PCa cells and demonstrated the following: firstly, Pro A selectively inhibited androgen-independent PCa (including PC3 and DU145) cell growth and induced cell apoptosis in vitro; secondly, Pro A significantly decreased cell motility and invasion of androgen-independent PCa cells; thirdly, Pro A enhanced the sensitivity of PCa cells to docetaxel; fourthly, Pro A significantly inhibited the growth of PCa xenografts in vivo and patient-derived organoids (PDO). In addition, RNA-sequencing analysis revealed that the antitumor effects of Pro A on androgen-independent PCa appeared to be achieved via driving the activation of endoplasmic reticulum stress. The antitumor effects of Pro A could be ameliorated by reactive oxygen species scavenger and ER stress inhibitors. Therefore, these data suggest that Pro A may provide a potential therapeutic option for the treatment of PCa, particularly CRPC.

Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

BACKGROUND: Cardiac glycosides are approved for the treatment of heart failure as Na+/K+ pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation. METHODS: Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry. RESULTS: At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression. CONCLUSION: Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.

Fluorescent Parkin Cell-Based Assay Development for the Screening of Drugs against Parkinson Disease.

Parkinson disease (PD) is a prevalent neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra, causing tremor and motor impairment. Parkin protein, whose mutants are the cause of Parkinson disease type 2 (PARK2), has been mechanistically linked to the regulation of apoptosis and the turnover of damaged mitochondria. Several studies have implicated aberrant mitochondria as a key contributor to the development of PD. In the attempt to discover new drugs, high-content cell-based assays are becoming more important to mimic the nature of biological processes and their diversifications in diseases and will be essential for lead identification and the optimization of therapeutic candidates. We have developed a novel fluorescence cell-based assay for high-content screening to find compounds that can promote the mitochondrial localization of Parkin without severe mitochondrial damage induction. In this work, this model was used to screen a library of 1280 compounds. After the screening campaign, the positive compounds were chosen for further testing, based on the strength of the initial response and lack of cytotoxicity. These results indicated that this Parkin cell-based assay is a robust (Z' > 0.5) and valid strategy to test potential candidates for preclinical studies.

Emprego de cardiotónico em sindrome de pré-excitaçäo ventricular: apresentaçäo de caso / Use of a cardiotonic agent in ventricular pre-excitation syndrome: report of a case

Um paciente que apresentou síndrome de Wolff-Parkinson-White, durante a digitaçäo, evidenciou fibrilaçäo atrial de alta freqüência ventricular. Discute-se a possibilidade de se empregar, nas síndromes de Wolff-Parkinson-White e de Lown-Ganong-Levine com insuficiência cardíaca, a procilaridina-A, ao invés de digital, face à diferença de atuaçäo sobre a via normal e a via anômala dos referidos cardiotônicos

Infarto do miocárdio associado à síndrome Wolff-Parkinson-White: aspectos eletrocardiográficos / Myocardial infarction associated with Wolff-Parkinson-White syndrome: electrocardiographic aspects

É apresentado um caso clínico em que os padröes clássicos eletrocardiográficos do infarto do miocárdio säo nitidamente mascarados pela presença de WPW. Esta provoca alteraçöes eletrocardiográficas somente no segmento ST-T, sendo observados somente os padröes clássicos da injúria, isquemia e necrose miocárdica, quando a conduçäo AV se processa pela via normal

Associaçäo de proscilaridina-A e verapamil por via oral no tratamento da angina do peito instável / Association of proscilaridine-A and verapamil by oral route in the treatment of unstable angina pectoris

A presente série de 14 casos de portadores de angina do peito instável, com a idade média de 53 anos (33-78 anos), admitidos em média com 10 dias (1-40 dias) após o início da síndrome clínica, foram submetidos à associaçäo de Proscilaridina-A (1,5-2,0 mg/dia) e Verapamil (240-320 mg/dia) por via oral e apresentaram os mesmos resultados obtidos com o emprego de outros cardiotônicos (Estronfatina-K ou G, Digoxina e Lanatosídeo-C) por via parenteral. A manutençäo tem sido registrada com a média de 30 meses (4-117 meses). Em apenas um paciente houve evoluçäo tardia para o enfarte do miocárdio 24 meses depois, para a insuficiência cardíaca congestiva aos 30 meses, registrando-se o óbito aos 60 meses de sua observaçäo. O tratamento assim instituído é destinado ao atendimento de nosso antigo conceito sobre o mecanismo eminentemente miogênico para o desencadeamento da angina do peito instável: falência miocárdiaca regional primária e isquemia miocárdica secundária, frente às permanentes condiçöes de pobre suprimento sanguíneo da aterosclerose coronária. O cardiotônico é encarado como o medicamento antienfarte e o dilatador coronário como o antianginoso e sua associaçäo tem sido apresentada nos últimos 13 anos como o tratamento mais eficaz e seguro da angina do peito instável; sua manutençäo representa a preservaçäo funcional do miocárdio isquêmico a longo prazo e propicia na maioria dos casos a reinstalaçäo de condiçäo clínica com características de angina do peito instável; enquanto muitos retornam à condiçäo de coronariopatia silenciosa

Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention--III. Profile of action of sodium 2-mercaptoethane sulfonate (mesna).

Mesna is a pharmacologically unremarkable, physiologically largely inert and almost totally non-toxic thio compound. It is rapidly eliminated renally and only slightly permeates into tissues. It has been shown experimentally that the bladder damage inducible in the rat by administration of oxazaphosphorine cytostatics can be successfully prevented by quite small doses of mesna. The detoxifying action of mesna is limited to the kidneys and the efferent urinary tract. The systemic effects of the oxazaphosphorines, however, remain unaffected. This applies particularly to the curative oncocidal efficacy of these compounds. It has also been shown experimentally that mesna does not affect the curative effects of other cytostatic drugs (doxorubicin, BCNU, methotrexate, vincristine). The efficacy of the cardiac glycoside proscillaridin is also not impaired by mesna.

[Meproscillarin in patients with renal failure and concomitant heart failure (author's transl)]. / Meproscillarin bei gleichzeitiger Nieren- und Herzinsuffizienz. Wirkungund Plasmakonzentration bei Dauernwendung.

Meproscillarin is a glycoside with a high bioavailability (about 70%) and an elimination independent of the renal function. It was to be investigated whether a good cardiac effectiveness can be demonstrated during oral long-term application of meproscillarin to patients with renal failure. 29 patients with renal failure of varying degree and concomitant heart failure were daily given an oral dose of 0.75 mg of meproscillarin over 14 days. The effectiveness of the glycoside was measured as change of the electromechanical systole (QS2c) and the quotient of the diameter of heart and thorax (C/T) from the 1st--15th day. The plasma levels of the glycoside were determined on the 1st, 8th, and 15th day. There was a significant shortening of QS2c (by mean = 27 ms, P less than 0.005) and a marked decrease in the size of the heart (P less than 0.0025); heart rate and PQ-interval were only insignificantly influenced. Plasma levels of 0.95 ng/ml were found after 8 days of treatment compared to 1.25 ng/ml after 15 days. As the pharmacokinetics of the glycoside is practically not influenced by the renal function, meproscillarin represents an alternative in the treatment of patients with heart failure and impaired renal function.

[Trial of a combination of proscillaridin A, thioridazine and Cori ester in the ambulatory treatment of some cardiopathies, especially senile types]. / Sperimentazione di una associazione di proscillaridina A, tioridazina ed estere di Cori nel trattamento ambulatoriale di alcune cardiopatie in particolare senili

The effect of an association of proscillaridin A, thioridazine and Cori ester in ambulatory management of certain heart diseases, particularly in aged subjects, was assessed. Satisfactory results were observed in 58.3% of cases, with significant improvement of cardiac erethism, psychomotor instability and sleep disturbances, as well as cardiac frequency and signs of myocardial insufficiency. It is felt that the association is of assistance in the treatment of certain heart diseases unaccompanied by frank signs of insufficiency, especially in aged subjects.

Multiclinical open studies on the effect of beta-methyldigoxin on congestive heart failure with atrial fibrillation.

Clinical open trials of beta-methyldigoxin were carried out in 15 institutions in order to examine the effect, usefulness and ease of its oral administration. In the case of oral digitalization with 0.2 mg, 3 times daily, an effect was obtained in all of 13 cases of congestive heart failure accompanied by atrial fibrillation or flutter. The average time and dose required for digitalization were about 50 hours and 1.27 mg respectively. In 9 of the 13 cases, the effect was achieved within 48 hours. The average maintenance does of beta-methyldigoxin in 102 cases of congestive heart failure with atrial fibrillation was 0.177 mg per day. About 75% of the cases were maintained with 0.15 to 0.2 mg. This range of dose of beta-methyldigoxin was much smaller than that of digoxin in our series. This can be ascribed to a higher absorption rate of beta-methyldigoxin from the digestive tract. Studies on the cases in which patients previously treated with other glycosides were switched over to beta-methyldigoxin revealed that 1 mg of beta-methyldigoxin is equivalent to 1.8 mg of digoxin or to 0.59 mg of digitoxin. The usefulness and ease of beta-methyldigoxin in maintenance was evaluated as being somewhat superior to other cardiac glycosides, according to the global judgement of the physicians. The observed side effects were similar to those of other glycosides in frequency and character.