Castration-Resistant Prostate Cancer: Mechanisms, Targets and Treatment

Mansinho, André; Macedo, Daniela; Fernandes, Isabel; Costa, Luís

doi:10.1007/978-3-319-99286-0_7

Cited by 69 publications

(69 citation statements)

References 44 publications

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“…1 Between 10% and 20% of men with metastatic PC develop CRPC within a 5-year period, and following the onset of such castration resistance the median survival time for these patients is just 14 months. 1,3 Chemotherapy remains the primary treatment for those with CRPC, 3 and entails the administration of an array of natural or synthetic pharmacological compounds that can help to disrupt tumor cell growth or division. Docetaxel is currently employed as a rst-line treatment for CRPC, as it has been shown to exhibit survival advantages for treated patients, but it is associated with negative side effects such as diarrhea, hair loss, and myelosuppression.…”

Section: Discussionmentioning

confidence: 99%

“…Docetaxel is currently employed as a rst-line treatment for CRPC, as it has been shown to exhibit survival advantages for treated patients, but it is associated with negative side effects such as diarrhea, hair loss, and myelosuppression. 3,7,12 DUl45 cells are androgen-independent human PC cells and are commonly used as a model for studies of CRPC. Novel therapeutic agents capable of treating CRPC are urgently needed.…”

Section: Discussionmentioning

confidence: 99%

“…1 PC treatments are typically treated via chemotherapy, radical prostatectomy, and hormone therapy, 2 with individuals with advanced disease often undergoing androgen deprivation therapy (ADT). 3 While initially e cacious in those with androgen-sensitive PC, most patients eventually exhibit ADT resistance such that their disease is reclassi ed as castration-resistant PC (CRPC) and has a poor prognosis. 2,3 As such, it is vital that novel treatments for CRPC be identi ed.…”

Section: Introductionmentioning

confidence: 99%

“…3 While initially e cacious in those with androgen-sensitive PC, most patients eventually exhibit ADT resistance such that their disease is reclassi ed as castration-resistant PC (CRPC) and has a poor prognosis. 2,3 As such, it is vital that novel treatments for CRPC be identi ed.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 Autophagy is a key catabolic process that is active in eukaryotic cells, 6 and it has recently been highlighted as a potentially viable therapeutic target for the treatments of CRPC. 3,7 The phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway is essential within cells 8 , with mTOR in particular serving to regulate activities such as cellular motility, proliferation, and autophagy. 9 ICA II has been shown to inhibit the COX-2/PGE 2 pathway and to induce mitochondria-dependent apoptosis in PC-3 PC cells.…”

Section: Introductionmentioning

confidence: 99%

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The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

Zhan

Xie

et al. 2020

Preprint

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Background The flavonol glycoside icariside Ⅱ (ICA II) has been shown to exhibit a range of anti-tumor properties. Herein we evaluated the impact of ICA II on the proliferation, motility, and autophagy activity of human prostate cancer cells, and we further evaluated the molecular mechanisms underlying these effects. Methods Herein, we treated DU145 human prostate cancer cells with a range of ICA II doses. We then evaluated the proliferative abilities of these cells via CCK-8 assay, whereas apoptosis and cell cycle status were assessed via flow cytometry. We further utilized wound healing and transwell assays to probe the impact of ICA II on migratory and invasive activities, while autophagy was assessed via laser confocal fluorescence microscopy. Western blotting was further utilized to measure LC3-II/I, Beclin-1, P70S6K, PI3K, AKT, mTOR, phospho-AKT, phospho-mTOR, and phospho-P70S6K levels, with RT-PCR being used to evaluate the expression of these same genes at the mRNA level. Results We found that ICA II was capable of mediating a dose- and time-dependent suppression of prostate cancer cell proliferative activity, while also causing these cells to enter a state of cell cycle arrest and apoptosis. We further determined that ICA II treatment was associated with significant impairment of prostate cancer cell migratory and invasive abilities, whereas autophagy was enhanced in treated cells relative to untreated controls. Levels of p-P70S6K, p-mTOR, p-AKT, and PI3K were all also decreased by ICA II. Conclusion Our results indicate that ICA II treatment is capable of suppressing human prostate tumor cell proliferation and disrupting migratory activity while enhancing autophagy through PI3K-AKT-mTOR signaling. As such, ICA II may be an ideal candidate drug for the treatment of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

Zhan

Xie

et al. 2020

Preprint

View full text Add to dashboard Cite

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Oncolytic adenovirus H101 ameliorate the efficacy of anti‐PD‐1 monotherapy in colorectal cancer

et al. 2022

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Background Immune checkpoint blockade therapy with anti‐programmed cell death (PD)‐1 antibodies provides therapeutic effect for many patients of various cancers but remains inadequate in colorectal cancer (CRC) patients. The present study aims to assess the efficacy of oncolytic adenovirus (OncoAd) in enhancing the anti‐PD‐1 treatment of CRC. Methods The estimating relative subsets of RNA transcripts algorithm was used for estimating the infiltrated immune cells in melanoma and CRC tissues. The efficacy of OncoAd with anti‐PD‐1 monotherapy was performed in a CT26 CRC mouse model in vivo. Flow cytometric analysis of peripheral blood and tumor tissues determined the difference anti‐tumor immune efficacy of OncoAd with anti‐PD‐1 monotherapy. Results The Cancer Genome Atlas database indicated that CD8+ T cells and regulatory T cells were significantly elevated in melanoma compared to CRC cohorts. Moreover, intratumor injection of oncolytic adenovirus enhanced T cell infiltration and decreased Treg percentages in the CT26 CRC colorectal cancer mouse model. Combinatorial OncoAd with anti‐PD‐1 antibody treatment markedly enhanced the anti‐tumor efficacy of anti‐PD‐1 by significantly decreasing the tumor volume and reducing tumor growth in a CRC mouse model. To the end, OncoAd treatment increased the CD8/Treg ratio, indicating that OncoAd intratumor injection ameliorate the anti‐tumor immune response of anti‐PD‐1 therapy. Conclusion The present study elucidates that OncoAd promotes intratumor T cell infiltration and improves anti‐PD‐1 immunotherapy, thereby providing a potent combinatorial therapeutic strategy for CRC.

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Orphan nuclear receptor RORγ confers doxorubicin resistance in prostate cancer

Gao

Guo

Wang

et al. 2020

Cell Biology International

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Prostate cancer (PCa) is a malignant tumor with an extremely high prevalence. Doxorubicin is the first‐line clinical treatment for castration‐resistant PCa. Clinically, relapse is almost inevitable due to the cancer cells' increasing resistance to doxorubicin. Our previous studies have revealed that retinoic acid‐related orphan nuclear receptor γ (RORγ) is a key protein for cancer progression and a promising target for PCa therapy. Though, RORγ's role and mechanism in doxorubicin‐resistant PCa remain unclear. To study the mechanism of doxorubicin resistance, we generated a doxorubicin‐resistant PCa cell line C4‐2B (C4‐2B DoxR) in this study, by culturing cells in an increasing doxorubicin concentration. Here, we show that RORγ expression was upregulated in C4‐2B DoxR cells compared with that in normal C4‐2B cells. The RORγ‐stably‐overexpressing PCa cell line constructed by lentiviral transfection showed an obvious improvement in doxorubicin resistance and a trend toward castration resistance. Furthermore, RORγ‐specific small molecule inhibitors XY018, GSK805, and SR2211 can significantly inhibit the proliferation of C4‐2B DoxR cells and promote their apoptosis. Collectively, these results have demonstrated the correlation between the upregulation of RORγ and the development of PCa's doxorubicin resistance, thus providing new ideas for solving the problem of chemotherapy drug resistance in PCa.

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Castration-Resistant Prostate Cancer: Mechanisms, Targets and Treatment

Cited by 69 publications

References 44 publications

The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

Oncolytic adenovirus H101 ameliorate the efficacy of anti‐PD‐1 monotherapy in colorectal cancer

Orphan nuclear receptor RORγ confers doxorubicin resistance in prostate cancer

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