Sandra Sigala - Academia.edu (original) (raw)

Papers by Sandra Sigala

BACKGROUND To present our experience of extended endovascular management for thromboangiitis obli... more BACKGROUND To present our experience of extended endovascular management for thromboangiitis obliterans (Buerger's disease) patients with critical limb ischemia (CLI). METHODS Between January 2005 and July 2010, a consecutive series of 17 Buerger's disease patients with CLI in 20 limbs were admitted and the diagnosis confirmed. The mean age of the patients was 41.5 years (standard error: ±1.7). All patients presented with history of smoking, one patient presented with hypertension, and eight patients presented with dyslipidemia. According to Rutherford classification, all patients were found to be between grades 3 and 5. Ultrasonography first, and angiography examination later, confirmed a severe arterial disease involving almost exclusively below-the-knee and foot arteries in all cases. A new approach for revascularization, defined as extended angioplasty of each tibial and foot artery obstruction, was performed to achieve direct perfusion of at least one foot artery. RESUL...

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH ... more 175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptom...

Breast cancer represents a heterogeneous group of diseases with varied biological features, behav... more Breast cancer represents a heterogeneous group of diseases with varied biological features, behavior, and response to therapy; thus, management of breast cancer relies on the availability of robust predictive and prognostic factors to support therapy decision-making. Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced, converting an inoperable to a surgical resectable cancer. Neoadjuvant trials, additionally, offer: 1) the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials; 2) to identify and validate the prognostic and predictive value of a marker with its association with clinical outcome in relation to the administered treatment. In this setting, thanks to new, affordable technologies which help to detail the molecular profiles of tumors, new trial designs based on new target therapies, like window-of-opportunity, are also suggested, as they represent the chance to identify tumor s...

BACKGROUND One of the paracrine/autocrine factors regulating prostate growth and differentiation ... more BACKGROUND One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characteri...

Biomedicines

Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like sid... more Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-α receptor and the induced conformational changes. The ER-α expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-α silencing was performed using two ER-α siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α...

Cancers

We evaluated tumor response at Computed Tomography (CT) according to three radiologic criteria: R... more We evaluated tumor response at Computed Tomography (CT) according to three radiologic criteria: RECIST 1.1, CHOI and tumor volume in 34 patients with metastatic adrenocortical carcinoma (ACC) submitted to standard chemotherapy. These three criteria agreed in defining partial response, stable or progressive disease in 24 patients (70.5%). Partial response (PR) was observed in 29.4%, 29.4% and 41.2% of patients according to RECIST 1.1, CHOI and tumor volume, respectively. It was associated with a favorable prognosis, regardless of the criterion adopted. The concordance of all the 3 criteria in defining the disease response identified 8 patients (23.5%) which displayed a very good prognosis: median progression free survival (PFS) and overall survival (OS) 14.9 and 37.7 months, respectively. Seven patients (20.6%) with PR assessed by one or two criteria, however, still had a better prognosis than non-responding patients, both in terms of PFS: median 12.3 versus 9.9 months and OS: 21 ver...

Cancers

Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regim... more Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-der...

Cancers

Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in... more Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1–12.8) and 18.7 months (95% CI: 14.6–22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified...

Endocrinology

Purpose Abiraterone acetate (AbiAc) inhibits tumor growth when administered to immunodeficient mi... more Purpose Abiraterone acetate (AbiAc) inhibits tumor growth when administered to immunodeficient mice engrafted with 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. Methods The experimental conditions for AbiAc absorption in AB zebrafish embryos as embryos number, AbiAc concentrations and absorption time-curve by LC-MS/MS were set up. The AbiAc effect on steroid production in AB zebrafish embryos was as well measured. ACC cells (NCI-H295R cell line, the primary cells ACC29 and the negative control cells SW13) were treated with the Dili fluorescent dye and about 240 cells/4 nl were injected in the subperidermal space of the yolk sac of AB zebrafish embryos (n=80±10). Cell area was measured with Noldus DanioScopeTM software. Results AbiAc absorption in AB zebrafish embryos was stage-dependent. Abiraterone (Abi) concentration decreased...

Journal of Oncology

Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventi... more Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, is nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most of radically resected ACC patients are destined to recur with local or metastatic disease. Numerous efforts aimed at identifying molecular alterations crucial for ACC pathogenesis have been extensively conducted, with the hope to develop new treatments. Indeed, multiple genes and pathways have been identified as potentially targetable in ACC patients; however, despite the strong preclinical rationale, translational findings to clinical trials led to date to disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules has been proposed as well, but results obtained in early studies indicate that ACC patients wo...

Naunyn-Schmiedeberg's Archives of Pharmacology

Molecular Neurobiology, 2017

The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons... more The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels. In the present study, hiPSCs generated from human dermal fibroblasts were used to produce midbrain DA (mDA) neurons, expressing the proper set of genes and proteins typical of authentic, terminally differentiated DA neurons. In this model, the expression and the functional properties of the human D2R/D3R were investigated with a combination of biochemical and functional techniques. We observed that in hiPSC-derived mDA neurons, the activation of D2R/D3R promotes the proliferation of neuronal progenitor cells. In addition, we found that D2R/D3R activation inhibits nicotine-stimulated DA release and exerts neurotrophic effects on mDA neurons that likely occur via the activation of PI3K-dependent mechanisms. Furthermore, D2R/D3R stimulation counteracts both the aggregation of alpha-synuclein induced by glucose deprivation and the associated neuronal damage affecting both the soma and the dendrites of mDA neurons. Taken together, these data point to the D2R/D3R-related signaling events as a biochemical pathway crucial for supporting both neuronal development and survival and protection of human DA neurons.

The Journal of Clinical Endocrinology & Metabolism, 2016

Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, whi... more Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis. Objective: To investigate the therapeutic use of AA in preclinical models of ACC. Design: AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice. Methods: Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed. Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice. Results: AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing. Conclusion: AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.

European journal of cancer (Oxford, England : 1990), Jul 1, 2016

Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic l... more Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic landscape for metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the effect of these novel androgen receptor pathway targeted agents in improving outcome of CRPC patients. A literature-based meta-analysis of randomized controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. The primary outcome was overall survival. The secondary end-points were time to the first symptomatic skeletal event, progression-free survival, prostatic antigen specific (PSA) response rate, time to PSA progression and safety. Pooled analysis from RCTs of novel androgen receptor pathway targeted agents revealed significantly increased overall surviva...

Journal of Pharmacovigilance, 2016

Recently, the expiry (or near expiration) of patents of these biological drugs prompted the pharm... more Recently, the expiry (or near expiration) of patents of these biological drugs prompted the pharmaceutical industries and governing bodies to replace them with non-innovator similar biologic drugs. These products are a new class of drugs intended to be comparable in both safety and efficacy measures to the reference drug and are generally referred as biosimilars. The major purpose of this replacement is to reduce the costs of production and time of approval for market entry. Biosimilars are also known as similar biological products, followup biologics, second entry biological, subsequent entry biologics, biogenerics, multisource products and off-patent biotech products [5]. Generally, the term biosimilar refers to a product which is biologically and functionally similar to the reference product, also called originator. By this definition, these drugs can be seen as comparable, but not identical to the reference product. These products cannot be deemed as a generic version of their originators, as they are not chemically derived single (small) molecular pharmaceutical entities, which are identical to the original drugs both in pharmaceutical equivalence (identical active substances) and bioequivalence (comparable pharmacokinetics

Anticancer research, 2016

Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but t... more Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction. ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure. Th...

BACKGROUND To present our experience of extended endovascular management for thromboangiitis obli... more BACKGROUND To present our experience of extended endovascular management for thromboangiitis obliterans (Buerger's disease) patients with critical limb ischemia (CLI). METHODS Between January 2005 and July 2010, a consecutive series of 17 Buerger's disease patients with CLI in 20 limbs were admitted and the diagnosis confirmed. The mean age of the patients was 41.5 years (standard error: ±1.7). All patients presented with history of smoking, one patient presented with hypertension, and eight patients presented with dyslipidemia. According to Rutherford classification, all patients were found to be between grades 3 and 5. Ultrasonography first, and angiography examination later, confirmed a severe arterial disease involving almost exclusively below-the-knee and foot arteries in all cases. A new approach for revascularization, defined as extended angioplasty of each tibial and foot artery obstruction, was performed to achieve direct perfusion of at least one foot artery. RESUL...

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH ... more 175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptom...

Breast cancer represents a heterogeneous group of diseases with varied biological features, behav... more Breast cancer represents a heterogeneous group of diseases with varied biological features, behavior, and response to therapy; thus, management of breast cancer relies on the availability of robust predictive and prognostic factors to support therapy decision-making. Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced, converting an inoperable to a surgical resectable cancer. Neoadjuvant trials, additionally, offer: 1) the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials; 2) to identify and validate the prognostic and predictive value of a marker with its association with clinical outcome in relation to the administered treatment. In this setting, thanks to new, affordable technologies which help to detail the molecular profiles of tumors, new trial designs based on new target therapies, like window-of-opportunity, are also suggested, as they represent the chance to identify tumor s...

BACKGROUND One of the paracrine/autocrine factors regulating prostate growth and differentiation ... more BACKGROUND One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characteri...

Biomedicines

Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like sid... more Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-α receptor and the induced conformational changes. The ER-α expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-α silencing was performed using two ER-α siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α...

Cancers

We evaluated tumor response at Computed Tomography (CT) according to three radiologic criteria: R... more We evaluated tumor response at Computed Tomography (CT) according to three radiologic criteria: RECIST 1.1, CHOI and tumor volume in 34 patients with metastatic adrenocortical carcinoma (ACC) submitted to standard chemotherapy. These three criteria agreed in defining partial response, stable or progressive disease in 24 patients (70.5%). Partial response (PR) was observed in 29.4%, 29.4% and 41.2% of patients according to RECIST 1.1, CHOI and tumor volume, respectively. It was associated with a favorable prognosis, regardless of the criterion adopted. The concordance of all the 3 criteria in defining the disease response identified 8 patients (23.5%) which displayed a very good prognosis: median progression free survival (PFS) and overall survival (OS) 14.9 and 37.7 months, respectively. Seven patients (20.6%) with PR assessed by one or two criteria, however, still had a better prognosis than non-responding patients, both in terms of PFS: median 12.3 versus 9.9 months and OS: 21 ver...

Cancers

Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regim... more Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-der...

Cancers

Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in... more Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1–12.8) and 18.7 months (95% CI: 14.6–22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified...

Endocrinology

Purpose Abiraterone acetate (AbiAc) inhibits tumor growth when administered to immunodeficient mi... more Purpose Abiraterone acetate (AbiAc) inhibits tumor growth when administered to immunodeficient mice engrafted with 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. Methods The experimental conditions for AbiAc absorption in AB zebrafish embryos as embryos number, AbiAc concentrations and absorption time-curve by LC-MS/MS were set up. The AbiAc effect on steroid production in AB zebrafish embryos was as well measured. ACC cells (NCI-H295R cell line, the primary cells ACC29 and the negative control cells SW13) were treated with the Dili fluorescent dye and about 240 cells/4 nl were injected in the subperidermal space of the yolk sac of AB zebrafish embryos (n=80±10). Cell area was measured with Noldus DanioScopeTM software. Results AbiAc absorption in AB zebrafish embryos was stage-dependent. Abiraterone (Abi) concentration decreased...

Journal of Oncology

Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventi... more Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, is nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most of radically resected ACC patients are destined to recur with local or metastatic disease. Numerous efforts aimed at identifying molecular alterations crucial for ACC pathogenesis have been extensively conducted, with the hope to develop new treatments. Indeed, multiple genes and pathways have been identified as potentially targetable in ACC patients; however, despite the strong preclinical rationale, translational findings to clinical trials led to date to disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules has been proposed as well, but results obtained in early studies indicate that ACC patients wo...

Naunyn-Schmiedeberg's Archives of Pharmacology

Molecular Neurobiology, 2017

The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons... more The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels. In the present study, hiPSCs generated from human dermal fibroblasts were used to produce midbrain DA (mDA) neurons, expressing the proper set of genes and proteins typical of authentic, terminally differentiated DA neurons. In this model, the expression and the functional properties of the human D2R/D3R were investigated with a combination of biochemical and functional techniques. We observed that in hiPSC-derived mDA neurons, the activation of D2R/D3R promotes the proliferation of neuronal progenitor cells. In addition, we found that D2R/D3R activation inhibits nicotine-stimulated DA release and exerts neurotrophic effects on mDA neurons that likely occur via the activation of PI3K-dependent mechanisms. Furthermore, D2R/D3R stimulation counteracts both the aggregation of alpha-synuclein induced by glucose deprivation and the associated neuronal damage affecting both the soma and the dendrites of mDA neurons. Taken together, these data point to the D2R/D3R-related signaling events as a biochemical pathway crucial for supporting both neuronal development and survival and protection of human DA neurons.

The Journal of Clinical Endocrinology & Metabolism, 2016

Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, whi... more Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis. Objective: To investigate the therapeutic use of AA in preclinical models of ACC. Design: AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice. Methods: Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed. Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice. Results: AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing. Conclusion: AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.

European journal of cancer (Oxford, England : 1990), Jul 1, 2016

Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic l... more Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic landscape for metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the effect of these novel androgen receptor pathway targeted agents in improving outcome of CRPC patients. A literature-based meta-analysis of randomized controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. The primary outcome was overall survival. The secondary end-points were time to the first symptomatic skeletal event, progression-free survival, prostatic antigen specific (PSA) response rate, time to PSA progression and safety. Pooled analysis from RCTs of novel androgen receptor pathway targeted agents revealed significantly increased overall surviva...

Journal of Pharmacovigilance, 2016

Recently, the expiry (or near expiration) of patents of these biological drugs prompted the pharm... more Recently, the expiry (or near expiration) of patents of these biological drugs prompted the pharmaceutical industries and governing bodies to replace them with non-innovator similar biologic drugs. These products are a new class of drugs intended to be comparable in both safety and efficacy measures to the reference drug and are generally referred as biosimilars. The major purpose of this replacement is to reduce the costs of production and time of approval for market entry. Biosimilars are also known as similar biological products, followup biologics, second entry biological, subsequent entry biologics, biogenerics, multisource products and off-patent biotech products [5]. Generally, the term biosimilar refers to a product which is biologically and functionally similar to the reference product, also called originator. By this definition, these drugs can be seen as comparable, but not identical to the reference product. These products cannot be deemed as a generic version of their originators, as they are not chemically derived single (small) molecular pharmaceutical entities, which are identical to the original drugs both in pharmaceutical equivalence (identical active substances) and bioequivalence (comparable pharmacokinetics

Anticancer research, 2016

Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but t... more Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction. ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure. Th...