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1.
Biomolecules ; 12(11)2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36358940

RESUMO

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Humanos , Masculino , Receptores Androgênicos/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Próstata/metabolismo , Transdução de Sinais , Microambiente Tumoral
2.
Cancer Res ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351060

RESUMO

Effective treatments for de novo and treatment-emergent small cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from advanced cancer patients, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a positron-emission tomography (PET) agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T cell engager (BiTE®) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable anti-tumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE® immunotherapy has significant anti-tumor activity in this aggressive prostate cancer subtype.

3.
Sensors (Basel) ; 22(22)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36433590

RESUMO

Atomic clock frequency jumps directly influence the accuracy and reliability of timekeeping systems. The necessary corrections are typically implemented by postprocessing mutual comparison data between multiple atomic clocks based on the overly strict assumption that these atomic clocks are independent of each other. This paper describes the concept of a mirror clock, which enables atomic clock frequency jumps to be identified in real time without any assumptions. By comparing whether the real measured data and a corresponding mirror clock prediction fall within a confidence interval determined by the uncertainty of past physical clock data, atomic clock frequency jumps can be effectively identified and corrected. The results of several experiments using three hydrogen masers verify that the precision and recall of simultaneous jump identification reach 96.41% and 73.49%, respectively.


Assuntos
Reprodutibilidade dos Testes , Incerteza
4.
J Gene Med ; : e3463, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36350267

RESUMO

BACKGROUND: Mammalian inositol 1,4,5-trisphosphate receptor (ITPR) genes encode ubiquitously expressed endoplasmic reticulum Ca2+ channels that have recently been shown to be closely linked to the pathogenesis of several cancers. However, few studies to date have explored associations between ITPR gene family single nucleotide polymorphisms (SNPs) and breast cancer risk. METHODS: In the present case-control study, 12 SNPs in the potential functional regions of the ITPR1, ITPR2, and ITPR3 genes were genotyped using an Illumina Infinium® Beadchip in 2095 Chinese women (1032 cases and 1063 controls). RESULTS: Multivariate logistic regression analyses indicated that a missense SNP in the ITPR3 coding region (rs2229642) was significantly related to breast cancer risk when using an additive model in this study (rs2229642-adjusted odds ratio = 1.40, 95% confidence interval = 1.12-1.74, p = 2.97 × 10-3 ). Expression quantitative trait loci analyses indicated that the SNP rs2229642 was associated with reduced ITPR3 expression levels (p = 3.2 × 10-7 ) and with marked reductions in the expressions of several proximal genes, including BAK1, GRM4, HLA-DOB, and UQCC2 (p = 0.013, 0.018, 3.4 × 10-3 , 3.8 × 10-5 ), suggesting that it may further regulate other genes associated with oncogenic susceptibility. Kaplan-Meier analyses indicated that the patients with higher ITPR3 expression exhibited significantly poorer outcomes compared to the patients with lower expression of this gene (hazard ratio = 1.11, 95% confidence interval = 1-1.23, p = 0.046). CONCLUSIONS: The results indicated that genetic variant in the coding region of ITPR3 gene may regulate the expressions of its host and some other cancer-related genes, as well as act as potential predictive biomarker for susceptibility to breast cancer in the Chinese population.

5.
Chem Commun (Camb) ; 58(86): 12090-12093, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36222090

RESUMO

A pH-responsive cascade nanoplatform based on ZIF-8 disintegrates in the weakly acidic tumor microenvironment to release MnO2, CaO2 and Ce6. The drugs can cyclically generate O2 for sonodynamic therapy, consume glutathione to tune the redox hemostasis, and produce cytotoxic ˙OH to kill tumor cells via chemical dynamics therapy.


Assuntos
Neoplasias da Mama , Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Feminino , Compostos de Manganês/farmacologia , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Óxidos , Microambiente Tumoral , Glutationa , Oxigênio , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral
6.
Nat Commun ; 13(1): 5345, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109521

RESUMO

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.


Assuntos
Fator de Transcrição E2F1 , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Receptores de Andrógenos/farmacologia , Benzamidas , Biópsia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/metabolismo , Humanos , Masculino , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , RNA , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
7.
Nat Commun ; 13(1): 4760, 2022 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-35963852

RESUMO

Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Androgênios , Sulfatos de Condroitina , Glicocálix/metabolismo , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Transdução de Sinais , Microambiente Tumoral
8.
Biochimie ; 200: 153-171, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35661748

RESUMO

Microvascular diseases are among the most clinically important diseases, and vascular abnormalities are central in the development of such diseases. Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, exerts antiangiogenic effects without affecting the structure and function of normal blood vessels. PEDF also has neurotrophic effects, which may be a potential direction for the future treatment of angiogenic diseases with lower side effects. Here, we review (i) the expression levels of PEDF in several important organs and clinically common microvascular diseases and (ii) the effects of its absence and presence on the vasculature and nerves, focusing on both angiogenic and neuroprotective aspects. These effects are both positive and negative, and have the potential to be exploited. Additionally, we summarize and compare various PEDF agents and their possible advantages and disadvantages as therapeutic agents, which, despite most still being in the experimental stage, may provide some new opportunities for future clinical treatments and interventions in PEDF-targeted microvascular diseases.


Assuntos
Serpinas , Proteínas do Olho/metabolismo , Humanos , Neovascularização Patológica , Fatores de Crescimento Neural/metabolismo , Serpinas/genética , Serpinas/metabolismo
9.
J Exp Clin Cancer Res ; 41(1): 214, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35773731

RESUMO

BACKGROUND: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. AIM OF REVIEW: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. KEY SCIENTIFIC CONCEPTS OF REVIEW: The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker.


Assuntos
Neoplasias da Próstata , RNA Longo não Codificante , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
10.
Exp Cell Res ; 417(2): 113213, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35618012

RESUMO

PURPOSE: The impairment of the coronary microcirculatory barrier caused by acute myocardial infarction (AMI) is closely related to poor prognosis. Recently, pigment epithelial-derived factor (PEDF) has been proven to be a promising cardiovascular protective drug. In this study, we demonstrated the protective role of PEDF in endothelial tight junctions (TJs) and the vascular barrier in AMI. MATERIALS AND METHODS: 2, 3, 5-triphenyltetrazolium chloride (TTC), echocardiography and immunofluorescence staining were used to observe the size of infarcted myocardium area and cardiac function in myocardial tissue, and the distribution of TJ proteins in human coronary endothelial cells (HCAEC). Dextran leakage assay and Transwell were used to assess the extent of vascular and HCAEC leakage. Polymerase chain reaction (PCR) and Western blot were used to detect TJ-related mRNA and protein, and signaling pathway protein expression. RESULTS: PEDF effectively reduced the infarction area and improved cardiac function in AMI rats, and lowered the leakage in AMI rats' angiocarpy and oxygen-glucose deprivation (OGD)-treated HCAEC. Furthermore, PEDF upregulated the expression of TJ mRNA and proteins in vivo and vitro. Mechanistically, PEDF inhibited the expression of phosphorylated low-density lipoprotein receptor-related protein 6 (p-LRP6) and active ß-catenin under OGD, thus suppressing the activation of the classical Wnt pathway. CONCLUSIONS: These novel findings demonstrated that PEDF maintained the expression of TJ proteins and endothelial barrier integrity by inhibiting the classical Wnt pathway during AMI.


Assuntos
Infarto do Miocárdio , Serpinas , Animais , Células Endoteliais/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Microcirculação , Infarto do Miocárdio/tratamento farmacológico , Fatores de Crescimento Neural , RNA Mensageiro , Ratos , Serpinas/genética , Serpinas/metabolismo , Serpinas/farmacologia , Junções Íntimas/metabolismo , Via de Sinalização Wnt
12.
Cells ; 11(9)2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35563856

RESUMO

Androgen deprivation therapy (ADT) is the standard therapy for men with advanced prostate cancer (PCa). PCa often responds to ADT and enters a dormancy period, which can be recognized clinically as a minimal residual disease. However, the majority of these patients will eventually experience a relapse in the form of castration-resistant PCa with poor survival. Therefore, ADT-induced dormancy is a unique time window for treatment that can provide a cure. The study of this well-recognized phase of prostate cancer progression is largely hindered by the scarcity of appropriate clinical tissue and clinically relevant preclinical models. Here, we report the utility of unique and clinically relevant patient-derived xenograft models in the study of the intrinsic immune landscape of dormant PCa. Using data from RNA sequencing, we have reconstructed the immune evasion mechanisms that can be utilized by dormant PCa cells. Since dormant PCa cells need to evade the host immune surveillance for survival, our results provide a framework for further study and for devising immunomodulatory mechanisms that can eliminate dormant PCa cells.


Assuntos
Antagonistas de Androgênios , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Análise de Sequência de RNA/métodos
13.
Drug Discov Today ; 27(8): 2181-2198, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35589014

RESUMO

Long noncoding RNAs (lncRNAs) are RNA molecules involved in gene regulation at transcriptional, post-transcriptional, and epigenetic levels. LncRNAs participate in regulating apoptosis and autophagy in pancreatic cancer (PCa) and can promote and/or decrease the proliferation rate of tumor cells. The metastasis of PCa cells is tightly regulated by lncRNAs and they can affect the mechanism of epithelial-mesenchymal transition (EMT) to modulate metastasis. The drug resistance of PCa cells, especially to gemcitabine, can be affected by lncRNAs. In addition, lncRNAs enriched in exosomes can be transferred among tumor cells to regulate their proliferation and metastasis. Antitumor compounds, such as curcumin and ginsenosides, can regulate lncRNA expression in PCa therapy. As we discuss here, the expression level of lncRNAs can be considered as both a diagnostic and prognostic tool in patients with PCa.


Assuntos
Neoplasias Pancreáticas , RNA Longo não Codificante , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
14.
J Thorac Oncol ; 17(8): 974-990, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35500836

RESUMO

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. RESULTS: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification. CONCLUSIONS: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Detecção Precoce de Câncer , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único
16.
J Hematol Oncol ; 15(1): 18, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35236381

RESUMO

Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.


Assuntos
Fenômenos Biológicos , MicroRNAs , Neoplasias , RNA Longo não Codificante , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , MicroRNAs/genética , Neoplasias/tratamento farmacológico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/uso terapêutico
17.
Front Oncol ; 12: 836159, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237526

RESUMO

BACKGROUND: It remains undetermined whether neuroticism affects the risk of lung cancer. Therefore, we performed complementary observational and Mendelian randomization (MR) analyses to investigate the association between neuroticism and lung cancer risk. METHODS: We included 364,451 UK Biobank participants free of cancer at baseline. Neuroticism was ascertained using the 12-item of Eysenck Personality Inventory Neuroticism Scale. Multivariable Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Two-sample MR analysis was carried out with summary genetic data from UK Biobank (374,323 individuals) and International Lung Cancer Consortium (29,266 lung cancer cases and 56,450 controls). Furthermore, we calculated a polygenic risk score of lung cancer, and examined the joint-effect and interaction between neuroticism and genetic susceptibility on lung cancer risk. RESULTS: During a median follow-up of 7.13 years, 1573 lung cancer cases were documented. After adjusting for smoking and other confounders, higher neuroticism was associated with an increased risk of lung cancer (HR per 1 SD=1.07, 95% CI: 1.02-1.12). Consistently, MR analysis suggested a causal effect of neuroticism on lung cancer risk (OR IVW=1.10, 95% CI: 1.03-1.17). Compared to individuals with low neuroticism and low PRS, those with both high neuroticism and high PRS had the greatest risk of lung cancer (HR=1.82, 95%CI: 1.51-2.20). Furthermore, there was a positive additive but no multiplicative interaction between neuroticism and genetic risk. CONCLUSIONS: Our findings suggest that neuroticism is associated with an elevated risk of incident lung cancer, which is strengthened by the genetic susceptibility to lung cancer. Further studies are necessary to elucidate underlying mechanisms.

18.
J Exp Clin Cancer Res ; 41(1): 105, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35317831

RESUMO

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.


Assuntos
Autofagia/genética , Neoplasias da Próstata/fisiopatologia , Humanos , Masculino
19.
Expert Opin Drug Deliv ; 19(4): 355-382, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35152815

RESUMO

INTRODUCTION: The application of doxorubicin (DOX) in cancer therapy has been limited due to its drug resistance and poor internalization. Graphene oxide (GO) nanostructures have the capacity for DOX delivery while promoting its cytotoxicity in cancer. AREAS COVERED: The favorable characteristics of GO nanocomposites, preparation method, and application in cancer therapy are described. Then, DOX resistance in cancer, GO-mediated photothermal therapy, and DOX delivery for cancer suppression are described. Preparation of stimuli-responsive GO nanocomposites, surface functionalization, hybrid nanoparticles, and theranostic applications are emphasized in DOX chemotherapy. EXPERT OPINION: GO nanoparticle-based photothermal therapy maximizes the anti-cancer activity of DOX against cancer cells. Besides DOX delivery, GO nanomaterials are capable of loading anti-cancer agents and genetic tools to minimize drug resistance and enhance the cytolytic impact of DOX in cancer eradication. To enhance DOX accumulation, stimuli-responsive (redox-, light-, enzyme- and pH-sensitive) GO nanoparticles have been developed for DOX delivery. Development of targeted delivery of DOX-loaded GO nanomaterials against cancer cells may be achieved by surface modification of polymers such as polyethylene glycol, hyaluronic acid, and chitosan. DOX-loaded GO nanoparticles have demonstrated theranostic potential. Hybridization of GO with other nanocarriers such as silica and gold nanoparticles further broadens their potential anti-cancer therapy applications.


Assuntos
Grafite , Nanopartículas Metálicas , Nanocompostos , Nanopartículas , Neoplasias , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ouro , Grafite/química , Humanos , Nanocompostos/química , Nanopartículas/química , Neoplasias/tratamento farmacológico
20.
Mol Cancer Res ; 20(5): 782-793, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35082166

RESUMO

Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors. IMPLICATIONS: We have established highly clinically relevant PDXs of ADT-induced dormant prostate cancer and identified two dormancy subtypes, leading to the development of a novel predicative gene signature that allows robust risk stratification of patients with prostate cancer to ADT or androgen-receptor pathway inhibitors.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Androgênios/uso terapêutico , Animais , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia
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