RESUMO
Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.
Assuntos
5'-Nucleotidase , Neoplasias da Próstata , Transdução de Sinais , Humanos , 5'-Nucleotidase/metabolismo , 5'-Nucleotidase/imunologia , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Microambiente Tumoral/imunologia , Adenosina/metabolismo , Imunoterapia/métodos , Terapia de Alvo MolecularRESUMO
OBJECTIVE: This study aims to investigate the correlation between serum testosterone levels after one month of treatment and prognosis in patients with high-volume disease metastatic prostate cancer (mPCa) who are undergoing combined androgen blockade therapy (CAB). METHODS: The clinical data of 199 patients with high-volume disease mPCa, diagnosed through biopsy pathology and imaging, were retrospectively analyzed from January 2010 to October 2022 in the Department of Urology at the First Affiliated Hospital of Xinjiang Medical University. Among these patients, 111 cases had a deep reduction in serum testosterone (< 0.7 nmol/l) after one month of treatment, while 88 cases did not achieve a deep reduction (≥ 0.7 nmol/l). The study utilized the Kaplan-Meier method to plot survival curves and employed the multifactor COX regression model to analyze independent risk factors. The risk factors with a significance level of P < 0.05 in the multivariate analysis were included in the nomogram prediction model. The accuracy of the model was assessed using the ROC curve and the calibration curve, while the net benefit for patients was evaluated through the decision curve analysis (DCA). RESULTS: The group that achieved deep testosterone reduction(DTR) had a higher proportion of PSA < 0.2 ng/ml and a greater PSA decline rate after six months of treatment (P < 0.05). The group that achieved DTR and the group that did not achieve DTR had a progression to castration resistant prostate cancer(CRPC) time of 17.93 ± 6.68 months and 13.43 ± 6.12 months, respectively (P < 0.001). The median progression-free survival time for the 2 groups were 18 months and 12 months, respectively (P < 0.001). The median overall survival times were 57 months and 32 months, respectively (P < 0.001). The median progression-free survival times were 18, 15, and 10 months for the group that achieved DTR within 1 month, the group that achieved DTR beyond 1 month but within 1 year, and the group that did not achieve DTR within 1 year, respectively (P < 0.001), and the median survival times were 57, 45, and 26 months, respectively (P < 0.001). COX multivariate analysis revealed that a testosterone level of ≥ 0.7 nmol/l at 1 month of treatment is an independent risk factor for the progression to CRPC and prognosis in patients with high-volume disease mPCa (P < 0.05). The risk of death in patients with a testosterone level of ≥ 0.7 nmol/l at 1 month of treatment was 2.087 times higher than that of patients with a level of < 0.7 nmol/l (P < 0.05). A nomogram prediction model was developed using independent risk factors, with the area under the ROC curve (AUC) for progression-free survival (PFS) at 12, 15, 18, and 21 months being 0.788, 0.772, 0.760, and 0.739, respectively. For 3 and 5 years, the AUCs for overall survival (OS) were 0.691 and 0.624. The calibration curve demonstrated good consistency between the model's predicted values and the actual outcomes. CONCLUSION: Patients with high-volume disease mPCa who receive CAB treatment may experience extended progression-free survival and overall survival if their serum testosterone levels are below 0.7 nmol/l after one month of treatment. The longer it takes to achieve DTR, the worse the patient's prognosis may be. The nomogram prediction model developed in this study demonstrates good predictive ability in assessing the progression and prognosis of high-volume disease mPCa.
Assuntos
Neoplasias da Próstata , Testosterona , Masculino , Humanos , Testosterona/sangue , Estudos Retrospectivos , Prognóstico , Idoso , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Pessoa de Meia-Idade , Antagonistas de Androgênios/uso terapêutico , Nomogramas , Metástase NeoplásicaRESUMO
Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.
Assuntos
Neoplasias da Próstata , Transdução de Sinais , Microambiente Tumoral , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/tratamento farmacológico , Animais , Quimiotaxia , Terapia de Alvo Molecular , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 µM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 µM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.
Assuntos
Antineoplásicos , Proliferação de Células , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90 , Histona Desmetilases , Organoides , Neoplasias da Próstata , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Organoides/efeitos dos fármacos , Organoides/patologia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Peixe-Zebra , Apoptose/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
BACKGROUND: Current prostate cancer treatments are associated with life-threatening side effects, prompting the search for effective and safer alternatives. Aspilia pluriseta Schweinf. ex Engl. has previously shown anticancer activity in lung and liver cancer cell lines. This study investigated its potential for prostate cancer. METHODS: A crude extract of A. pluriseta root was prepared using dichloromethane/methanol (1:1 v/v) and partitioned into hexane, ethyl acetate, and water fractions. The MTT assay was used to assess the antiproliferative activity of the fractions. The active fractions were tested at 6.25-200 µg/ml on human prostate cancer DU-145 cells and non-cancerous Vero E6 cells. Qualitative phytochemical and gas chromatography-mass spectrometry (GC-MS) analyses were conducted to identify chemical compounds. Network pharmacology was employed to predict molecular targets and modes of action of the identified chemical compounds, with subsequent validation through molecular docking and real-time PCR. RESULTS: Active extracts included crude dichloromethane/methanol, hexane, and ethyl acetate fractions, inhibiting DU-145 cell proliferation with IC50 values of 16.94, 20.06, and 24.14 µg/ml, respectively. Selectivity indices were determined to be 6.04 (crude), 3.62 (hexane), and 6.68 (ethyl acetate). Identified phytochemicals comprised phenols, terpenoids, flavonoids, tannins, sterols, and saponins. GC-MS analysis revealed seventy-nine (79) compounds, with seven (7) meeting ideal drug candidate parameters; their hub gene targets included MAPK3, MAPK1, IL6, TP53, ESR1, PTGS2, MMP9, MDM2, AR, and MAP2K1, implicating regulation of PI3K/Akt, MAPK, and p53 signaling pathways as potential modes of action. Core compounds such as 1-heneicosanol, lanosterol, andrographolide, and retinoic acid exhibited strong binding activities, particularly lanosterol with MAPK21 (-9.7 kcal/mol), ESR1 (-8.9 kcal/mol), and MAPK3 (-8.8 kcal/mol). Treatment with A. pluriseta downregulated AR expression and upregulated p53, while also downregulating CDK1 and BCL-2 and upregulating caspase-3. CONCLUSIONS: A. pluriseta extracts inhibited DU-145 cell growth without causing cellular toxicity, suggesting great potential for development as an anti-prostate cancer agent. However, further in vitro and in vivo experiments are recommended.
Assuntos
Antineoplásicos Fitogênicos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Extratos Vegetais , Neoplasias da Próstata , Neoplasias da Próstata/tratamento farmacológico , Masculino , Humanos , Linhagem Celular Tumoral , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , AnimaisRESUMO
OBJECTIVES: The high costs of cancer care can cause significant harm to patients and society. Prostate cancer, the leading nonskin malignancy in men, is responsible for the second-highest out-of-pocket (OOP) payments among all malignancies. Multiple first-line treatment options exist for metastatic castration-resistant prostate cancer (mCRPC); although their costs vary substantially, comparative effectiveness data are limited. There is little evidence of how gross payments made by insurers and OOP payments made by patients differ by treatment and health plan type and how these payment differences relate to utilization. STUDY DESIGN: Retrospective cohort study. METHODS: We used IBM MarketScan databases from 2013-2019 to identify men with prostate cancer who initiated treatment with 1 of 6 drugs approved for first-line treatment of mCRPC. We calculated and compared gross and OOP payments and drug utilization across drug and insurance plan types. RESULTS: We identified 4298 patients who met our inclusion criteria. Insurer payments varied substantially by first-line therapy but were similar across different health plan types, except for docetaxel. OOP payments for a given first-line therapy, in contrast, varied by health plan type. Utilization of first-line therapies varied by plan type in unadjusted analyses, but not after adjusting for patient characteristics. CONCLUSIONS: The extent to which patient OOP payments for drugs reflect differences in gross payments made by insurers varies across health insurance plan types. However, even though OOP payments for the same treatment differ across plan types, treatment choice is not significantly different across type of health insurance after controlling for patient characteristics.
Assuntos
Gastos em Saúde , Seguro Saúde , Humanos , Masculino , Estudos Retrospectivos , Idoso , Gastos em Saúde/estatística & dados numéricos , Estados Unidos , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/economia , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Docetaxel/uso terapêutico , Docetaxel/economiaRESUMO
Prostate cancer (PC) is a significant cause of mortality in men worldwide, hence the need for a comprehensive understanding of the molecular mechanisms underlying its progression and resistance to treatment. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a critical player in cancer biology, including PC. This review explores the multifaceted role of HO-1 in PC, encompassing its function, regulation, and implications in cancer therapy. HO-1 influences cell proliferation, anti-apoptotic pathways, angiogenesis, and the tumor microenvironment, thereby influencing tumor growth and metastasis. HO-1 has also been associated with therapy resistance, affecting response to standard treatments. Moreover, HO-1 plays a significant role in immune modulation, affecting the tumor immune microenvironment and potentially influencing therapy outcomes. Understanding the intricate balance of HO-1 in PC is vital for developing effective therapeutic strategies. This review further explores the potential of targeting HO-1 as a therapeutic approach, highlighting challenges and opportunities. Additionally, clinical implications are discussed, focusing on the prognostic value of HO-1 expression and the development of novel combined therapies to augment PC sensitivity to standard treatment strategies. Ultimately, unraveling the complexities of HO-1 in PC biology will provide critical insights into personalized treatment approaches for PC patients.
Assuntos
Heme Oxigenase-1 , Neoplasias da Próstata , Microambiente Tumoral , Humanos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Animais , Proliferação de CélulasRESUMO
Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100-1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as 68Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., 177Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma.
Assuntos
Antígenos de Superfície , Glutamato Carboxipeptidase II , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Glicosilação , Terapia de Alvo Molecular/métodosRESUMO
BACKGROUND: Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first- and second-generation, non-covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. PURPOSE: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR-R1PCa cell lines to second-generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). METHODS: 2D and 3D mono- and co-cultures of cancer cells, and cancer-associated fibroblasts (CAFs) were used to mimic tumor-stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real-time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. RESULTS: The FGFRis were more effective in mono-cultures of the cancer cells compared with co-cultures with CAFs. The FRS2αi was specifically effective in co-cultures with CAFs but was not cytotoxic to CAF mono-cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p-FRS2α, p-ERK1/2, and activated apoptosis as monitored by cleaved caspase-3 activity in a concentration-dependent manner in the co-cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co-cultures as indicated by their reduced size and Ki67 expression. CONCLUSIONS: CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co-cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next-generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.
Assuntos
Fibroblastos Associados a Câncer , Proliferação de Células , Técnicas de Cocultura , Receptores de Fatores de Crescimento de Fibroblastos , Humanos , Masculino , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/farmacologiaRESUMO
The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.
Assuntos
Proliferação de Células , Progressão da Doença , Sinergismo Farmacológico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Metiltransferases , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Metiltransferases/metabolismo , Metiltransferases/antagonistas & inibidores , Animais , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/farmacologiaRESUMO
Prostate cancer is the leading cause of cancer death in men. Some studies suggest that selenium Se (+4) may help prevent prostate cancer. Certain forms of Se (+4), such as Selol, have shown anticancer activity with demonstrated pro-oxidative effects, which can lead to cellular damage and cell death, making them potential candidates for cancer therapy. Our recent study in healthy mice found that Selol changes the oxidative-antioxidative status in blood and tissue. However, there are no data on the effect of Selol in mice with tumors, considering that the tumor itself influences this balance. This research investigated the impact of Selol on tumor morphology and oxidative-antioxidative status in blood and tumors, which may be crucial for the formulation's effectiveness. Our study was conducted on healthy and tumor-bearing animal models, which were either administered Selol or not. We determined antioxidant enzyme activities (Se-GPx, GPx, GST, and TrxR) spectrophotometrically in blood and the tumor. Furthermore, we measured plasma prostate-specific antigen (PSA) levels, plasma and tumor malondialdehyde (MDA) concentration as a biomarker of oxidative stress, selenium (Se) concentrations and the tumor ORAC value. Additionally, we assessed the impact of Selol on tumor morphology and the expression of p53, BCL2, and Ki-67. The results indicate that treatment with Selol influences the morphology of tumor cells, indicating a potential role in inducing cell death through necrosis. Long-term supplementation with Selol increased antioxidant enzyme activity in healthy animals and triggered oxidative stress in cancer cells, activating their antioxidant defense mechanisms. This research pathway shows promise in understanding the anticancer effects of Selol. Selol appears to increase the breakdown of cancer cells more effectively in small tumors than in larger ones. In advanced tumors, it may accelerate tumor growth if used as monotherapy. Therefore, further studies are necessary to evaluate its efficacy either in combination therapy or for the prevention of recurrence.
Assuntos
Antioxidantes , Estresse Oxidativo , Neoplasias da Próstata , Masculino , Animais , Estresse Oxidativo/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Camundongos , Antioxidantes/farmacologia , Selênio/farmacologia , Modelos Animais de Doenças , Compostos de Selênio/farmacologia , Malondialdeído/metabolismo , Antígeno Prostático Específico/sangue , Linhagem Celular Tumoral , Glutationa Peroxidase/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Chronic inflammation is a recognized risk factor for various cancers, including prostate cancer (PCa). We aim to explore the potential protective effects of aged black garlic extract (ABGE) against inflammation-induced prostate damage and its impact on prostate cancer cell lines. We used an ex vivo model of inflammation induced by Escherichia coli lipopolysaccharide (LPS) on C57BL/6 male mouse prostate specimens to investigate the anti-inflammatory properties of ABGE. The gene expression levels of pro-inflammatory biomarkers (COX-2, NF-κB, and TNF-α, IL-6) were measured. Additionally, we evaluated ABGE's therapeutic effects on the prostate cancer cell lines through in vitro functional assays, including colony formation, tumorsphere formation, migration assays, and phosphorylation arrays to assess the signaling pathways (MAPK, AKT, JAK/STAT, and TGF-ß). ABGE demonstrated significant anti-inflammatory and antioxidant effects in preclinical models, partly attributed to its polyphenolic content, notably catechin and gallic acid. In the ex vivo model, ABGE reduced the gene expression levels of COX-2, NF-κB, TNF-α, and IL-6. The in vitro studies showed that ABGE inhibited cell proliferation, colony and tumorsphere formation, and cell migration in the prostate cancer cells, suggesting its potential as a therapeutic agent. ABGE exhibits promising anti-inflammatory and anti-cancer properties, supporting further investigation into ABGE as a potential agent for managing inflammation and prostate cancer.
Assuntos
Anti-Inflamatórios , Alho , Camundongos Endogâmicos C57BL , Extratos Vegetais , Próstata , Neoplasias da Próstata , Masculino , Animais , Extratos Vegetais/farmacologia , Alho/química , Neoplasias da Próstata/tratamento farmacológico , Camundongos , Anti-Inflamatórios/farmacologia , Humanos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Antioxidantes/farmacologia , NF-kappa B/metabolismo , Lipopolissacarídeos , Água/químicaRESUMO
INTRODUCTION: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists. PATIENTS AND METHODS: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed. RESULTS: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months. CONCLUSIONS: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed.
Assuntos
Carbolinas , Carcinoma Neuroendócrino , Compostos Heterocíclicos de 4 ou mais Anéis , Neoplasias da Próstata , Humanos , Masculino , Carbolinas/administração & dosagem , Carbolinas/uso terapêutico , Carbolinas/efeitos adversos , Idoso , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Resultado do Tratamento , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Estudos Retrospectivos , Intervalo Livre de ProgressãoRESUMO
INTRODUCTION: Prostate cancer is one of the most prevalent malignancies affecting men globally, with a significant impact on health-related quality of life (HRQOL). With the recent therapeutic advancements and improvements in survival, there is a need to understand the determinants of HRQOL in metastatic prostate cancer patients to optimize treatment strategies for quality of life as the number of survivors increases. The aim of this study was to identify clinical variables that affect HRQOL and its domains in patients with metastatic prostate cancer. METHODS: We conducted a cross-sectional questionnaire-based study in patients diagnosed with metastatic prostate cancer at a tertiary cancer center in India. Baseline clinical features, treatment details, and completed Functional Assessment of Cancer Therapy-Prostate (FACT-P), composed of FACT-general (FACT-G) and prostate cancer-specific concerns subscale (PCS) and FACT-P Trial Outcome Index (FACT-P TOI) questionnaires, were collected. The mean total, as well as individual domain scores, were calculated. Additionally, these were stratified by the current treatment being received by patients. Linear regression was used to identify independent factors affecting HRQOL in these patients. RESULTS: Of the 106 enrolled patients, 84 completed the FACT-P questionnaire and were included in the analysis. The median age was 66 years, and at the time of assessment, 3 patients (3.6%) were receiving androgen deprivation therapy only, 53 patients (63.1%) were on ADT + androgen receptor-targeted agents (ARTAs), and 18 patients (21.4%) patients received ADT + chemotherapy. The mean (±standard deviation) of the FACT-P TOI score was 70.33 (±15.16); the PCS subscale was the most affected, followed by functional well-being. Patients on chemotherapy scored significantly higher on PCS, but the composite scores were not significantly different. Univariable regression identified obesity (body mass index > 25 kg/m2) and duration of first-line treatment as significant predictors of better HRQOL; however, obesity was the only independent predictor in multivariable analysis (ß = 8.2; 95% confidence interval, 1.2 to 15.0; p = 0.022). Obesity also independently predicted a better FACT-P and its physical well-being domain score and PCS. CONCLUSION: Prostate cancer patients experience impaired QoL, especially in the prostate cancer-specific and functional well-being domains. Lower BMI is an independent predictor of poor QoL, and this requires efforts to assess the impact of strategies to manage the nutritional status of patients with metastatic disease on QoL outcomes.
Assuntos
Neoplasias da Próstata , Qualidade de Vida , Humanos , Masculino , Estudos Transversais , Neoplasias da Próstata/psicologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Inquéritos e Questionários , Idoso , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
Although Androgen Deprivation Therapy (ADT) is effective in controlling prostate cancer (PCa) and increasing survival, it is associated with a myriad of side effects that cause significant morbidity. Previous research has shown that PCa patients starting on ADT are neither fully informed nor well-equipped to manage the breadth of ADT's side effects. The ADT Educational Program (a 1.5 h interactive class plus a book) was developed as an evidence-based resource for patients dealing with ADT. Our aim here was to compare the efficacy of an online version of the class with a previously assessed in-person version of the class. Using mixed MANOVAs within a non-randomized comparison design, we assessed: (1) changes in patients' experiences of self-efficacy to manage and bother associated with side effects approximately 10 weeks after attending a class, and (2) potential differences in these variables between online and in-person class formats. Side effect bother decreased from pre- to post-class but did not differ between in-person (n = 94) and online (n = 137) class cohorts. While self-efficacy to manage side effects was slightly higher post-class in both cohorts, the increase was not statistically significant. Average self-efficacy ratings were significantly higher among in-person versus online class participants (p < 0.05; ηp2 = 0.128). Both online and in-person classes are associated with a significant reduction in the severity of side effect bother reported by PCa patients, suggesting non-inferiority of online versus in-person formats. Online classes offer greater accessibility to the program for patients outside the reach of in-person classes, increasing the availability of the program to more PCa patients and family members across Canada.
Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Autoeficácia , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Canadá , Neoplasias da Próstata/tratamento farmacológico , Idoso , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodosRESUMO
BACKGROUND: Prostate cancer (PCa) management commonly involves the utilization of prostate radiotherapy (PRT), pelvic nodal radiotherapy (PNRT), and androgen deprivation therapy (ADT). However, the potential association of these treatment modalities with bone marrow (BM) suppression remains inadequately reported in the existing literature. This study is designed to comprehensively evaluate the risk of myelosuppression associated with PRT, shedding light on an aspect that has been underrepresented in prior research. MATERIALS AND METHODS: We conducted a retrospective analysis of 600 patients with prostate cancer (PCa) treated with prostate radiotherapy (PRT) at a single oncology center between 2007 and 2017. Patients were categorized into four cohorts: PRT alone (n = 149), PRT + ADT, (n = 91), PRT + PNRT (n = 39), and PRT + PNRT + ADT (n = 321). To assess the risk of myelosuppression, we scrutinized specific blood parameters, such as hemoglobin (HGB), white blood cells (WBCs), neutrophils (NEUT), lymphocytes (LYM), and platelets (PLT) at baseline, mid-treatment (mRT), immediately post-RT (pRT), 1 month post-RT (1M-pRT), and 1 year post-RT (1Y-pRT). The inter-cohort statistical significance was evaluated with further stratification based on the utilized RT technique {3D conformal radiotherapy (3D-CRT), and intensity-modulated radiation therapy (IMRT)}. RESULTS: Significant statistical differences at baseline were observed in HGB and LYM values among all cohorts (p < 0.05). Patients in the PRT + PNRT + ADT cohort had significantly lower HGB at baseline and 1M-pRT. In patients undergoing ADT, BMS had a significant impact at 1M-pRT {odds ratio (OR) 9.1; 95% Confidence Interval (CI) 4.8-17.1} and at 1Y-pRT (OR 2.84; CI 1.14-7.08). The use of 3D-CRT was linked to reduced HGB levels in the PRT + PNRT + ADT group at 1 month pRT (p = 0.015). Similarly, PNRT significantly impacted BMS at 1M-pRT (OR 6.7; CI 2.6-17.2). PNRT increased the odds of decreased WBC counts at 1Y-pRT (OR 6.83; CI: 1.02-45.82). Treatment with any RT techniques (3D-CRT or IMRT), particularly in the PRT + PNRT and PRT + PNRT + ADT groups, significantly increased the odds of low LYM counts at all time points except immediately pRT (p < 0.05). Furthermore, NEUT counts were considerably lower at 1M-pRT (p < 0.05) in the PRT + PNRT + ADT group. PLT counts were significantly decreased by PRT + PNRT + ADT at mRT (OR 2.57; 95% CI: 1.42-4.66) but were not significantly impacted by the RT technique. CONCLUSIONS: Treatment with PRT, ADT, PNRT, and 3D-CRT is associated with BMS. Despite this statistically significant risk, no patient required additional interventions to manage the outcome. While its clinical impact appears limited, its importance cannot be underestimated in the context of increased integration of novel systemic agents with myelosuppressive properties. Longer follow-up should be considered in future studies.
Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Antagonistas de Androgênios/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Pelve/efeitos da radiação , Medula Óssea/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/efeitos adversosRESUMO
Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 µM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Isoquinolinas , Neoplasias da Próstata , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Masculino , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologiaRESUMO
Propofol has become a microtubule-stabilizing drug for prostate cancer (PC) therapy, but propofol resistance impairs the therapeutic effect. This study aimed to explore the regulatory mechanism of propofol in the pathogenesis of PC through mechanisms involving N6-methyladenosine (m6A) modification. The changes in PC cell malignancy were evaluated by means of transwell, cell counting kit 8 (CCK-8), western blotting and tumour xenograft model assays. Long noncoding RNA TRHDE-AS1 and m6A methyltransferase METTL14 expression levels were determined via reverse transcription quantitative polymerase chain reaction (RT-qPCR). The m6A modification of TRHDE-AS1 which was mediated by METTL14 was confirmed by conducting methylated RNA immunoprecipitation (MeRIP) assay. We observed that propofol (200 µM) inhibited PC cell malignancy in vivo and in vitro, elucidating that it impaired cell proliferation, migration and tumour growth but induced apoptosis. TRHDE-AS1 expression was observed to be lower in PC cells and tissues, and propofol induced TRHDE-AS1 upregulation in PC cells. Propofol was capable of reversing the tumour-promoting effect of TRHDE-AS1 knockdown in PC cells. Additionally, METTL14 was upstream of TRHDE-AS1 to induce m6A modification of TRHDE-AS1 in PC cells. Collectively, our results show that propofol prevents PC progression by upregulating TRHDE-AS1 expression and METTL14 is involved in the m6A modification of TRHDE-AS1. These findings suggest that TRHDE-AS1 may be a potential therapeutic target for the improvement of propofol's therapeutic effect.