Frontiers in Pharmacology
·
2024
·
IF 4.4
Chen Xinlu,Gong Luyao,Wang Yuanyuan,Ye Chen,Guo Huanhuan,Gao Shen,Chen Jiyuan,Wang Zhuo,Gao Yuan
Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis.Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod.Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio.Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.
研究领域:
肿瘤学
·
分子生物学
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纳米技术
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免疫治疗
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8488
·
IF 13.3
Jiyuan Chen,Luyao Gong,Simeng Cao,Guanshan Song,Yeheng Peng,Yuanyuan Wang,Yan-Ru Lou,Teemu J Murtola,Yao Wu,Ganjun Yu,Yuan Gao
Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8 + T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.
研究领域:
肿瘤学
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分子治疗
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药理学
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生物信息学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Lele Xu,Yuting Chen,Tao Wu,Jiaqi Fan,Yuying Hu,Xuefeng Gao,Yuliang Wang,Tao Chen,Xueting Zhao,Min Zeng,Fei Wang,Qingyou Zheng,Xiaojuan Pei,Dinglan Wu
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m 6 A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m 6 A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m 6 A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
·
2023
·
IF 3.7
Zhen Wang,Jing Zou,Le Zhang,Hongru Liu,Bei Jiang,Yi Liang,Yuzhe Zhang
Background: Almost all patients treated with androgen deprivation therapy (ADT) eventually develop castration-resistant prostate cancer (CRPC). Our research aims to elucidate the potential biomarkers and molecular mechanisms that underlie the transformation of primary prostate cancer into CRPC. Methods: We collected three microarray datasets ( {"type":"entrez-geo","attrs":{"text":"GSE32269","term_id":"32269"}} GSE32269 , {"type":"entrez-geo","attrs":{"text":"GSE74367","term_id":"74367"}} GSE74367 , and {"type":"entrez-geo","attrs":{"text":"GSE66187","term_id":"66187"}} GSE66187 ) from the Gene Expression Omnibus (GEO) database for CRPC. Differentially expressed genes (DEGs) in CRPC were identified for further analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Weighted gene coexpression network analysis (WGCNA) and two machine learning algorithms were employed to identify potential biomarkers for CRPC. The diagnostic efficiency of the selected biomarkers was evaluated based on gene expression level and receiver operating characteristic (ROC) curve analyses. We conducted virtual screening of drugs using AutoDock Vina. In vitro experiments were performed using the Cell Counting Kit-8 (CCK-8) assay to evaluate the inhibitory effects of the drugs on CRPC cell viability. Scratch and transwell invasion assays were employed to assess the effects of the drugs on the migration and invasion abilities of prostate cancer cells. Results: Overall, a total of 719 DEGs, consisting of 513 upregulated and 206 downregulated genes, were identified. The biological functional enrichment analysis indicated that DEGs were mainly enriched in pathways related to the cell cycle and metabolism. CCNA2 and CKS2 were identified as promising biomarkers using a combination of WGCNA, LASSO logistic regression, SVM-RFE, and Venn diagram analyses. These potential biomarkers were further validated and exhibited a strong predictive ability. The results of the virtual screening revealed Aprepitant and Dolutegravir as the optimal targeted drugs for CCNA2 and CKS2, respectively. In vitro experiments demonstrated that both Aprepitant and Dolutegravir exerted significant inhibitory effects on CRPC cells ( p < 0.05), with Aprepitant displaying a superior inhibitory effect compared to Dolutegravir. Discussion: The expression of CCNA2 and CKS2 increases with the progression of prostate cancer, which may be one of the driving factors for the progression of prostate cancer and can serve as diagnostic biomarkers and therapeutic targets for CRPC. Additionally, Aprepitant and Dolutegravir show potential as anti-tumor drugs for CRPC.
研究领域:
肿瘤学
·
分子生物学
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生物信息学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Xinzhi Xu,Jing Fu,Yujie Wan,Jiaqi Gong,Ruixia Hong,Jia Tang,Qizhi Wang,Ying Li,Kaifeng Huang,Yizhe Zhong,Hang Zhou,Jichun Yang,Yang Luo,Fang Li
Ultrasound (US) -responsive therapy shows promise for castration-resistant prostate cancer (CRPC), which is associated with high mortality and limited treatment options. Especially, the combination of sono-triggered local tumor destruction with immunotherapy may offer synergistic benefits, while the efficacy of such sono-immunotherapy is hindered by the inherently “immune-cold” tumor microenvironment (TME) of CRPC. Herein, a sono-triggered in situ nano-vaccine (SATNAV) is developed for precise CRPC sono-immunotherapy via multi-reprograming the immunosuppressive TME. On one hand, under high-intensity focused ultrasound (HIFU) irradiation, the perfluoropentane (PFP)-containing SATNAV undergoes acoustic droplet vaporization and cavitation, realizing satisfactory ablation of solid tumors and producing an in-situ vaccine effect with immunogenic cell death (ICD). On the other hand, the immunosuppressive microenvironment of CRPC is regulated in multiple aspects for a favorable prognosis. SATNAV improves tumor-selective accumulation by Neuropilin-2 (NRP-2)-targeted recognition and may help attenuate secretory immune evasion associated with exosomal programmed death-ligand 1 (PD-L1). Moreover, SATNAV delivers a redox-responsive stimulator of interferon genes (STING) agonist (MSA-2) to immunosuppressive regions and collaborates with sono-triggered to achieve immune activation. This system suppresses exosomal PD-L1-related immune escape, activates the STING-TBK1-IRF3 pathway, and enhances immune cell infiltration, thereby suggesting the potential to induce immunological memory and ultimately multi-remodel the immunosuppressive TME of CRPC. SATNAV represents a novel strategy that integrates sono-triggered cavitation ablation with immune activation for CRPC treatment.
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DOI
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-14
·
IF 6.4
Jin Shengkai,Zhou Yuhua,Lv Jing,Lu Yichen,Zhang Yuwei,Li Menglu,Feng Ninghan
Background A close relationship exists between castration-resistant prostate cancer (CRPC) and histidine metabolism by gut microbes. However, the effects of the histidine metabolite imidazole propionate (IMP) on prostate cancer (PCa) and its underlying mechanisms are not well understood.Methods We first assessed the effects of IMP on cell proliferation and migration at the cellular level. Subsequently, we investigated the mechanism of action of IMP using transcriptome sequencing, qPCR, and Western blot analysis. Finally, we validated our findings in vivo using a mouse model.Results Histidine had no effect on PCa cell proliferation; however, IMP significantly inhibited the proliferation and migration of PC3 and DU145 cells. Mechanistic studies indicate that IMP exerts its effects by upregulating PDZK1 expression, which subsequently inhibits the phosphorylation of the PI3K-AKT pathway.Conclusion sIn conclusion, IMP significantly inhibits the progression of PCa, offering new insights into potential treatments for CRPC.
研究领域:
肿瘤学
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微生物学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2022
·
IF 3.94
Zheng Xu,Luwei Xu,Yuzheng Ge,Hongbin Sun,Jiageng Zhu,Quanliang Dou,Ruipeng Jia
Background: Cabazitaxel has been applied to the treatment of castration-resistant prostate cancer (CRPC), but the molecular mechanism remained to be fully understood. Methods: After treatment with Cabazitaxel alone or in combination with ionizing radiation (IR), CRPC cell viability, proliferation and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay, colony formation, and flow cytometry, respectively. Tumor volume was measured after the establishment of animal xenograft model. Relative expressions of proteins related to apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase 3) and phosphoinositide 3-kinase (PI3K)/AKT pathway were measured by Western blot, and the phosphorylated-PI3K/PI3K and p-AKT/AKT ratios were determined as well. Results: Cell viability and proliferation were suppressed, and apoptosis was promoted in CRPC cells after Cabazitaxel treatment alone, accompanied with upregulated expressions of Bax and cleaved caspase 3 and downregulated Bcl-2 expression. Also, a single treatment with Cabazitaxel resulted in suppression of PI3K/AKT pathway activation, along with downregulated expressions of p-PI3K and p-AKT and a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Meanwhile, Cabazitaxel enhanced the effects of IR on suppressing survival and promoting apoptosis in CRPC cells through downregulating Bcl-2 and upregulating Bax and cleaved caspase 3. However, Cabazitaxel suppressed IR-induced PI3K/AKT pathway activation via downregulating p-PI3K and p-AKT, leading to a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Furthermore, Cabazitaxel further promoted the effects of IR on suppressing tumor growth in vivo . Conclusion: Cabazitaxel inhibited the proliferation and promoted the apoptosis and radiosensitivity of CRPC cells, which is related to the suppression of PI3K/AKT pathway, providing a therapeutic method for CRPC in clinical practice.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2017
·
IF 2.399
Lin Yu,Xiaofeng Wu,Min Chen,Huarong Huang,Yan He,Huaqian Wang,Dongli Li,Zhiyun Du,Kun Zhang,Susan Goodin,Xi Zheng
Background : Docetaxel is the first-line treatment for castration-resistant prostate cancer (CRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminishes its efficacy in high-dose monotherapy. YK-4-279 is a small molecule inhibitor of ETV1 that plays an important role in the progression of prostate cancer. The aim of this study was to evaluate the hypothesis that the combination of docetaxel and YK-4-279 will have a synergistic effect on inhibiting growth and accelerating apoptosis in human prostate cancer cells. Methods : Cell growth assessed using CCK-8 and trypan blue exclusion assays. Cell apoptosis was determined by morphological assessment in cells stained with propidium iodide. Standard scratch migration and Matrigel-coated transwell invasion assays were used to assess cell migration and invasion, respectively. Western blotting was used to investigate the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in prostate cancer cells. Results : The combination of low-dose docetaxel and YK-4-279 synergistically inhibited growth and induced apoptosis in human prostate cancer cells. The combination also more efficiently suppressed the migration and invasion of LNCaP and PC-3 cells. The combination of low-dose docetaxel and YK-4-279 caused a stronger decrease in the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in LNCaP cells and of p-Akt, Bcl-2, and p-STAT3 in PC-3 cells compared with either drug alone. Conclusions : These data suggest that the combination of docetaxel and YK-4-279 may be an effective approach for inhibiting the growth and metastasis of prostate cancer. This could permit a decrease in the docetaxel dose necessary for patients with CRPC and thereby lower its systemic toxicity.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Epigenomics
·
2022
·
IF 4.357
Hanlin Li,Yanjie Yang,Jianpeng Yu,Boya Zhang,Xuanrong Chen,Shimiao Zhu,Yuanjie Niu,Zhiqun Shang
Aims: We aimed to determine whether intronic circRNA acts as a molecular sponge in castration-resistant prostate cancer (CRPC). Materials & methods: A gene chip technique was used to conduct sequencing. A qPCR experiment was performed to verify the result. Radioimmunoprecipitation, RNA pull-down and dual-luciferase reporter assays were performed to particularly expound its function. Verification of downstream effects was carried out through qPCR and western blot, and a xenograft assay was performed in vivo for verification. Results: Intronic circRNA hsa_circ_0092339 in the nucleus was highly expressed in CRPC cell lines. hsa_circ_0092339 did not regulate the expression of its parental gene. hsa_circ_0092339 functions like a molecular sponge, preventing degradation of C-MYC mRNA by absorbing hsa-mir-940. Conclusion: hsa_circ_0092339 plays a critical role in CRPC through targeting C-MYC indirectly by absorbing hsa-mir-940.Plain language summaryOur research breaks the mold by investigating a novel function of RNA and a novel regulatory mechanism. Our research provides a new therapeutic target for prostate cancer treatment and broadens the understanding of prostate cancer.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
前列腺癌
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Xinyu Shan,Xiang Li,Zhenyu Luo,Qing Lin,Yichao Lu,Mengshi Jiang,Junlei Zhang,Jiaxin Huang,Lin Xie,Xuemeng Guo,Xu Liu,Yingying Shi,Yu Liu,Hang Yin,Fuchun Yang,Lihua Luo,Jian You
When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and in vivo safety. To fully exploit this in situ LLC platform with both injectability and sprayability, we focused on the treatment of both hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC). For HSPC, we found that spraying leuprolide and a cabazitaxel-loaded LLC platform on the tumor bed after resection greatly reduced tumor metastatic rate and prolonged the survival time. Besides, for CRPC, our results demonstrated that although leuprolide (a kind of drug for castration) alone could hardly limit the progression of CRPC with low MHC-I expression, its combination with cabazitaxel in our LLC platform achieved a significantly better tumor-inhibiting and anti-recurrent efficacy than single cabazitaxel-loaded LLC platform, owing to enhanced CD4+ T cell infiltration in tumors and immune-potentiating cytokines. In conclusion, our dual-functional and clinically achievable strategy might provide a treating solution toward both HSPC and CRPC.
研究领域:
药学
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肿瘤学
·
药物递送系统
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生物医学工程
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免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Vaccines
·
2021
·Vol. 9
·期 7
·786
·
IF 4.422
Linpei Guo,Hui Xie,Zheng Zhang,Zhun Wang,Shuanghe Peng,Yuanjie Niu,Zhiqun Shang
(1) Background: There are currently limited treatments for castration-resistant prostate cancer. Immunotherapy involving Sipuleucel-T has increasingly drawn attention for prostate cancer management. BCG plays a vital role in treating bladder cancer, mainly by inducing immune activation, but is rarely used for prostate cancer. (2) Methods: The TCGA database, PCR, and Western blotting were used to analyze the expression of STEAP1 in mouse and human tissues. Then, we constructed a fusion protein vaccine withMycobacterium tuberculosisAg85B and three repeated octapeptide epitopes of a six-transmembrane epithelial antigen of the prostate 1 (STEAP1186-193), Ag85B-3×STEAP1186-193. The uptake of the fusion protein vaccine by DCs was evaluated by confocal microscopy, and DC markers were detected using flow cytometry after incubation with the fusion protein. The immune response against prostate cancer was evaluated by the LDH assay and xenografts in vitro and in vivo. Then, the tumor microenvironment was determined using IHC and ELISA. In addition, the epitope was mutated using CRISPR-Cas9 to illustrate that the fusion protein elicited immunization against STEAP1. (3) Results: The TCGA database analysis, PCR, and Western blotting showed that STEAP1 was highly expressed in human and murine prostate cancer. After the uptake of the purified fusion protein vaccine by DCs, CD11c, CD80, CD86, and MHC II were upregulated and triggered a cytotoxic T lymphocyte (CTL) response against TRAMP-C1 and RM1 cells in vitro. Furthermore, the fusion protein vaccine inhibited tumor growth and improved the tumor microenvironment in vivo, with more CD3+cells and fewer FOXP3+cells in the tumor. Serum IFN-γ and IL-2 were significantly higher than in the control group, while IL-4 expression was lower, indicating that the fusion protein vaccine activated Th1 immunity. The immune response against prostate cancer was greatly suppressed when the antigen targets were knocked out using CRISPR-Cas9. (4) Conclusion: In summary, our results provide the first evidence that a vaccine based on a fusion protein consisting of Ag85B and a prostate cancer octapeptide epitope with complete Freund’s adjuvant (CFA), triggers a robust immune response and inhibits tumor growth in murine prostate cancer.Keywords:Ag85B;Mycobacteriumtuberculosis;STEAP1;six-transmembrane epithelial antigen of the prostate 1;immune response;prostate cancer;castration-resistant prostate cancer (CRPC)
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症免疫疗法
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）