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COVID-19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated and evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real-life context is strongly needed. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Antivirais/farmacologia , COVID-19/terapia , Reposicionamento de Medicamentos , Humanos , Imunização Passiva , SARS-CoV-2 , Soroterapia para COVID-19RESUMO
BACKGROUND: General and local anaesthetics are widely used during surgery. These drugs have peculiar safety profiles, being commonly associated with mild and reversible local adverse drug reactions (ADRs), but also with more severe and systemic ADRs, including respiratory and cardiovascular depression and anaphylaxis. METHODS AND OBJECTIVES: We carried out a descriptive analysis of Individual Case Safety Reports (ICSRs) sent to the Campania Regional Centre of Pharmacovigilance (Southern Italy) from 2001 to 2021 that reported general or local anaesthetics as suspected drugs, with the aim of describing their overall characteristics, focussing on the ADRs' seriousness and distribution by System Organ Class (SOC) and Preferred Term (PT). RESULTS: A total of 110 ICSRs documenting general or local anaesthetics were sent to the Italian pharmacovigilance database during 20 years of spontaneous reporting activities in the Campania region. ADRs mainly occurred in patients with a median age of 48 years and in a slightly higher percentage of men. ADRs were more commonly classified as not serious and had a favourable outcome. In terms of ADRs' distribution by SOC and PT, both general and local anaesthetics were associated with general and cutaneous disorders, with common ADRs that included lack of efficacy, rash, and erythema. In addition, general anaesthetics were associated with the occurrence of respiratory ADRs, while local anaesthetics were associated with the occurrence of nervous ADRs. CONCLUSION: Even though a limited number of ICSRs documenting anaesthetics-induced ADRs were retrieved from the Italian spontaneous reporting database in the Campania region, we believe that the continuous monitoring of these drugs is highly recommended, especially among the frail population.
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Since December 2019 SARS-Cov-2 was found responsible for the disease COVID-19, which has spread worldwide. No specific therapies/vaccines are yet available for the treatment of COVID-19. Drug repositioning may offer a strategy and a number of drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab. This paper describes the main pharmacological properties of such drugs administered to patients with COVID-19, focusing on their antiviral, immune-modulatory and/or anti-inflammatory actions. Where available, data from clinical trials involving patients with COVID-19 are reported. Preliminary clinical trials seem to support their benefit. However, such drugs in COVID-19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. Nevertheless, while waiting for effective preventive measures i.e. vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. Their results will help us in defining the best way to treat COVID-19 and reducing its symptoms and complications. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
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Antivirais/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
Receptor-activator of nuclear-factor -κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK-positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Time-to-Bone-Metastasis-Progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and Time-to-Bone-Metastasis-Progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness.
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Neoplasias da Mama , Denosumab/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , Ligante RANK/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Projetos PilotoRESUMO
Tobacco smoke contains more than 4000 detectable substances, such as polycyclic aromatic hydrocarbons, nicotine, carbon monoxide and heavy metals, which are considered powerful enzymatic inducers that have notable influence on the efficacy and tolerability of many medications through complex pharmacokinetic and pharmacodynamic interactions. As a result, adjustments of drug dosages are required in smokers, both if they continue to smoke or if they quit after smoking cessation treatment. The purpose of this review is to examine the main drug interactions with tobacco smoke clinically relevant, with a closer look on patients developing oncologic diseases.
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Neoplasias Pulmonares/terapia , Fumar/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Apoptose , Transformação Celular Neoplásica , Citocromo P-450 CYP2A6/genética , Citocromo P-450 CYP2A6/metabolismo , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Lesões Pré-Cancerosas/etiologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Abandono do Hábito de Fumar , Resultado do TratamentoRESUMO
Endothelial progenitor cells (EPCs) may concur to endogenous vascular repair. Previous studies have reported that statin treatment increases EPC levels. We investigated whether this occurs in patients on long-term statin treatment who underwent percutaneous coronary interventions (PCIs). In a phase A study, 53 patients (atorvastatin reload [AR] 80 mg 12 hours before + 40 mg 2 hours before PCI, n = 27; placebo [P], n = 26) were evaluated for EPC mobilization as CD45dim/CD34+/CD133+/KDR+ cell number by flow cytometry. Assays were run at randomization (12 hours before PCI, R), immediately before PCI (T0) at 8 (T8) and 24 hours (T24). In phase B study, 50 patients (AR, n = 25; P, n = 25) were evaluated for early colony formation by Hill colony forming unit (CFU) assay, with sampling at randomization and 24 hours later. In phase A, EPCs levels were similar at randomization between 2 arms (0.23% [0.14 to 0.54] of total events in AR vs 0.22% [0.04 to 0.37] in P group; p = 0.33). At PCI, EPC levels were higher in AR arm (0.42% [0.06 to 0.30] vs 0.19% [0.06 to 030]; p = 0.009). Higher EPC levels in AR group were also found at 8 and 24 hours. In phase B, EPC CFUs/well numbers at randomization were similar in the 2 arms (8 [6 to 12] in AR vs 12 [6 to 20] in P group, p = 0.109). EPC CFU/well at 24 hours became significantly higher in AR arm (17 [10 to 23] vs 5 [2 to 13], p = 0.002). In conclusion, high-dose AR before PCI in patients on long-term statin therapy promptly increases EPCs mobilization, which are capable of early colony formation and may contribute to cardioprotection.
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Síndrome Coronariana Aguda/tratamento farmacológico , Atorvastatina/administração & dosagem , Células Progenitoras Endoteliais/citologia , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/patologia , Síndrome Coronariana Aguda/cirurgia , Idoso , Contagem de Células , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
Gall bladder cancer (GBC), and intrahepatic and extrahepatic (perihilar or distal bile duct's) cholangiocarcinomas (CCA) are usually diagnosed in locally advanced or node-positive stage, with a short survival rate. Thus, it appears essential to explore novel strategies for improving disease downstage and radical surgery. Chemoradiotherapy followed by liver transplantation seems to be one of the most promising approaches for intrahepatic or perihilar disease while chemotherapy with novel radiotherapy techniques (such stereotactic body radiation) emerged as an attractive preoperative treatment in distal diseases. In this paper, we will review currently available knowledge about neoadjuvant treatment of biliary tract cancers (BTC) paying attention to challenges that make this type of management in clinical practice difficult.
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Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. In this article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.
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Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , HumanosRESUMO
INTRODUCTION: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. PATIENTS AND METHODS: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. RESULTS: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. DISCUSSION: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
INTRODUCTION: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting. AREAS COVERED: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development. EXPERT OPINION: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.
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Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Denosumab/uso terapêutico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Taxa de Sobrevida , Microambiente TumoralRESUMO
Abiraterone acetate (ABI) is associated not only with a significant survival advantage in both chemotherapy-naive and -treated patients with metastatic castration-resistant prostate cancer (mCRPC), but also with a delay in time to development of Skeletal Related Events and in radiological skeletal progression. These bone benefits may be related to a direct effect on prostate cancer cells in bone or to a specific mechanism directed to bone microenvironment. To test this hypothesis we designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI.Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients.These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity.
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Androstenos/farmacologia , Antineoplásicos/farmacologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Fosfatase Alcalina/sangue , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Peptídeos/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
Liposarcoma (LPS) is the most common soft tissue sarcoma. It has been demonstrated that mir-155 was the most overexpressed miRNA in well-differentiated LPS(WDLPS)/dedifferentiated LPS (DDLPS). The aim of this study is to evaluate the involvement of Dicer, Drosha and mir-155 in development of LPS and their possible role in stratification of different histological subtypes. Dicer, Drosha and mir-155 mRNA levels were analyzed in formalin-fixed paraffin-embedded specimens from patients diagnosed with 62 LPS and compared with samples of adipose tissues of healthy donors. The experimental data were obtained using qRT-PCR comparing Dicer, Drosha and mir-155 expression levels in tumor samples versus normal fat. The tumor samples from LPS patients showed a significantly lower Dicer expression versus normal adipose tissue, while Drosha levels did not differ. Concerning mir155 expression levels, our results demonstrated a significant mir-155 up-regulation in all LPS subtypes versus normal adipose tissue except for WDLS. These findings demonstrate for the first time that Dicer is deregulated in LPS and show that mir-155 is differentially expressed in LPS subgroups and it could be a promising tool to improve LPS disease stratification and differential diagnosis.
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RNA Helicases DEAD-box/biossíntese , Lipossarcoma/metabolismo , MicroRNAs/biossíntese , Ribonuclease III/biossíntese , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Humanos , Lipossarcoma/genética , Lipossarcoma/patologia , Masculino , MicroRNAs/genética , Análise em Microsséries , Estudos Retrospectivos , Ribonuclease III/genética , Ribonuclease III/metabolismoRESUMO
The development of bone metastases requires multistep and multicellular machinery consisting not only of processes shared with any type of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to the particular bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). MiRNAs are highly conserved, small RNAs molecules that regulate gene expression. The functional consequence of miRNA deregulation lies in the mRNA targets whose expression is altered. MiRNA networks acting as upstream regulators of these genes interfere with the initial steps of tumor local invasion and cancer cell intravasation, mainly by regulating the epithelial-mesenchymal transition, the motility, invasiveness and survival abilities of these cells. The miRNA-mediated regulation on the steps of bone tropism, anchorage, homing and finally bone colonization is more tissue specific, being dependent on the expression pattern of target miRNAs in bone marrow sinusoids, bone cells and microenvironment. In that, miRNA specific expression signatures that can distinguish between primary tumors from their corresponding bone metastases might be determinants of clinical aggressiveness. In this review, we focus on the current advances on functions and molecular mechanisms by which miRNAs exert their biological roles in regulating bone metastases development.
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Neoplasias Ósseas , RNA Neoplásico , Microambiente Tumoral , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , RNA Neoplásico/genética , RNA Neoplásico/metabolismoRESUMO
The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.
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Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Serina-Treonina Quinases TOR/genética , Carcinoma de Células Renais/patologia , Everolimo , Regulação Neoplásica da Expressão Gênica , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
PURPOSE: Published data demonstrated that zoledronic acid (ZOL) exhibits antiangiogenetic effects. A promising tool for monitoring antiangiogenic therapies is the measurement of circulating endothelial cells (CECs) and circulating endothelial precursor cells (CEPs) in the peripheral blood of patients. Our aim was to investigate the effects of ZOL on levels of CECs and CEPs in localized prostate cancer. METHODS: Ten consecutive patients with a histologic diagnosis of low-risk prostate adenocarcinoma were enrolled and received an intravenous infusion of ZOL at baseline (T0), 28 days (T28) and 56 days (T56). Blood samples were collected at the following times: T0 (before the first infusion of ZOL), T3 (72 h after the first dose), T28, T56 (both just before the ZOL infusion) and T84 (28 days after the last infusion of ZOL) and CEC/CEP levels were directly quantified by flow cytometry at all these time points. RESULTS: Our analyses highlighted a significant reduction of mean percentage of CECs and CEPs after initiation of ZOL treatment [p = 0.014 (at day 3) and p = 0.012 (at day 84), respectively]. CONCLUSION: These preliminary results demonstrate that ZOL could exert an antiangiogenic effect in early prostate cancer through CEP and CEC modulation.
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Inibidores da Angiogênese/farmacologia , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Células Endoteliais/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Células-Tronco/efeitos dos fármacos , Idoso , Movimento Celular , Células Endoteliais/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Ácido ZoledrônicoRESUMO
Endothelial Progenitor Cells (EPCs), a minor subpopulation of the mononuclear cell fraction in peripheral blood, play a critical role in cancer development as they contribute to angiogenesis-mediated pathological neovascularization. In response to tumor cytokines, including VEGF, EPCs mobilize from the bone marrow into the peripheral circulation and move to the tumor bed where they incorporate into sprouting neovessels. In the present study, we evaluated the effects of everolimus (Afinitor, Novartis), a rapamycin analogue, alone or in combination with chloroquine, a 4-alkylamino substituted quinoline family member, one of the autophagy inhibitors, on EPCs biological functions. We found that either everolimus or chloroquine induce growth inhibition on EPCs in a dose-dependent manner after 72 h from the beginning of incubation. The combined administration of the two drugs to EPC was synergistic in inducing growth inhibition; in details, the maximal pharmacological synergism between everolimus and chloroquine in inducing growth inhibition on EPCs cells was recorded when chloroquine was administered 24 h before everolimus. Moreover, we have studied the mechanisms of cell death induced by the two agents alone or in combination on EPCs and we have found that the synergistic effect of combination on EPC growth inhibition was paralleled by increased apoptosis induction and reduced autophagy. These effects occurred together with biochemical features that are typical of reduced autophagic death such as increased co-immunoprecipitation between Beclin 1 and Bcl-2. Chloroquine antagonized the inhibition of the activity of Aktâ4EBP1 axis mediated by everolimus and at the same time it blocked the feed-back activation of Erk-1/2 induced by RAD in EPCs. These data suggest a new strategy in order to block angiogenesis in tumours in which this process plays a key role in both the sustainment and spreading of cancer cells.
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Cloroquina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Sirolimo/análogos & derivados , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proteína Beclina-1 , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Everolimo , Humanos , Proteínas de Membrana/metabolismo , Modelos Biológicos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sirolimo/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
PURPOSE: The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients. METHODS: Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n=116 and n=50, respectively) and from patients with diverticulosis as control group (n=20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome. RESULTS: The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P<.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P<.0001) and overall survival (OS) (P=.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P=.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P=.011), lower organs involvement (RR 0.79; P=.034) and low Dicer expression (RR 0.71; P=.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome. CONCLUSION: These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Bevacizumab , Neoplasias Colorretais/patologia , RNA Helicases DEAD-box/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease III/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Recent studies have been reported that angiogenesis suppression may play a role in developing bisphosphonate-related osteonecrosis of the jaw (B-ONJ). According to these evidence we evaluated the role of VEGF as predictive marker of B-ONJ onset. Of the 81 patients, 6 developed B-ONJ following bisphosphonate treatment. These patients showed a strongest decrease in VEGF circulating levels at day 7 and at day 21 after the first administration. These data demonstrated for the first time that the anti-angiogenic properties of bisphosphonates are directly linked to B-ONJ pathogenesis and serum VEGF levels could represent an effective early predictive marker.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Humanos , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
INTRODUCTION: Bone marrow-derived cells (BMDC) localize in premetastatic niche through chemokines and integrins signals and establish clusters that precede the arrival of even single metastatic tumor cell at distant site. CSCs demonstrate an increased metastatic propensity and would seem likely candidates for the acquisition of migratory capabilities and propagation of heterogeneous tumor cell populations to different target organs. Sonic Hedgehog (SHH), FOXM1 and Notch pathways and signaling molecules such as integrin and chemokine could dictate their fate. AREAS COVERED: In this review, the molecular mechanisms of premetastatic niche onset are summarized. EXPERT OPINION: Premetastatic niche is defined as a fertile microenvironment that forms in metastatic target organ and facilitates the invasion, survival and/or proliferation of metastatic tumor cells, providing a novel mechanism for the promotion of metastasis. Drugs targeting premetastatic niche could represent a new promising therapeutic approach in the treatment of bone metastases.
Assuntos
Metástase Neoplásica , Neoplasias/tratamento farmacológico , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco NeoplásicasRESUMO
PML regulates a wide range of pathways involved in tumorigenesis, such as apoptosis, which is also one of the main mechanisms through which oxaliplatin and fluoropyrimidine exert their antineoplastic activity. The present study aims to investigate PML expression as a predictive factor of oxaliplatin/fluoropyrimidine therapy efficacy. Seventy-four metastatic colorectal cancer patients who received oxaliplatin/floropyrimidine-based first line therapy have been included in this retrospective study. PML expression was assessed by immunohistochemistry. PML down-regulation was detected in 39 (52.7%) patients (14 complete and 25 partial PML loss). RR was significantly lower (25.6%) in patients with PML down-regulation than in patients with preserved PML expression (60%) (P = 0.006). Median TTP was 5.5 months when PML was down-regulated versus 11.9 months in case of preserved PML expression (P < 0.0001). A statistical significant difference was also detected in OS (15.6 and 24.5 months, respectively, P = 0.003). The impact of PML down-regulation on TTP and OS was statistically significant also in a multivariate model. This study represents the first evidence of a possible correlation between PML protein expression and outcome of metastatic colorectal cancer patients treated with oxaliplatin/fluoropyrimidine-based first line therapy.