Docetaxel for Metastatic Hormone-sensitive Prostate Cancer: Urgent Need to Minimize the Risk of Neutropenic Fever

Tsao, Che‐Kai; Galsky, Matthew D.; Oh, William K.

doi:10.1016/j.eururo.2016.06.041

Cited by 16 publications

(12 citation statements)

References 10 publications

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“…We and others have previously identified a vital role of PrLZ in the progression of CRPC, which was associated with an increased PrLZ/AR interaction 8 , 11 , 12 . Docetaxel is widely used as the standard first-line therapeutic strategy for CRPC patients 2 , 20 , but resistance eventually develops. In the present study, we demonstrate that overexpression of PrLZ confers resistance to docetaxel-induced apoptosis and autophagy in PCa cells.…”

Section: Discussionmentioning

confidence: 99%

“…Prostate cancer (PCa) is one of the most lethal malignancies, accounting for an estimated 26,120 deaths in the United States 1 . Chemotherapy with docetaxel, a member of the taxane family, is used as the first-line standard chemotherapy treatment and has been determined to show a survival advantage in metastatic castration-resistant prostate cancer (mCRPC) patients 2 . However, a substantial proportion of patients with mCRPC treated with docetaxel eventually become refractory and progress due to the development of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy

Zeng¹,

Liu²,

Fan³

et al. 2018

Theranostics

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Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients. However, a substantial proportion of patients eventually becomes refractory due to drug resistance. The detailed mechanisms remain unclear. We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC. In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway.Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo. Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay. The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression.Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo. Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy. Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo.Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy

Zeng¹,

Liu²,

Fan³

et al. 2018

Theranostics

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“…Die Frage, ob nun Docetaxel oder eher Abirateron zur Kombination mit der ADT eingesetzt werden soll, kann zum aktuellen Zeitpunkt nicht abschließend geklärt werden. Vorteile von Abirateron sind sicher das Fehlen chemotherapietypischer Nebenwirkungen wie Neutropenie, Fatigue, Nausea, Alopezie oder Neuropathie [19]. Demgegenüber stehen jedoch mineralokortikoide Nebenwirkungen wie Hypertonie, Hypokaliämie als auch Nebenwirkungen wie respiratorische Störungen und ein Anstieg der Leberwerte [11].…”

Section: Chemohormontherapie Oder Die Kombinationstherapie Aus Adt + unclassified

Medikamentöse Tumortherapie des metastasierten nicht kastrationsresistenten Prostatakarzinoms

Jentzmik¹,

Christian²

2017

Klinikarzt

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ZusammenfassungÜber Jahrzehnte galt die Androgendeprivation (ADT) als alleiniger Standard beim fortgeschrittenen metastasierten hormonnaiven Prostatakarzinom in der Erstlinientherapie. 2016 wurde die Therapie durch die Kombination der Androgendeprivation mit dem Chemotherapeutikum Docetaxel revolutioniert. Durch diese Chemohormontherapie konnte eine signifikante Verlängerung des progressionsfreien Überlebens und des Gesamtüberlebens erreichet werden.Aktuell konnte in der STAMPEDE- und der LATITUDE-Studie ein signifikanter Zusatznutzen für eine Kombination von Abirateron plus Prednison plus Androgendeprivation gezeigt werden. Sowohl das Gesamtüberleben, das progressionsfreie Überleben als auch die Zeit bis zum radiologischen Progress konnten im Vergleich zur alleinigen Hormontherapie verbessert werden.Der Überlebensvorteil der Kombinationstherapie von ADT + Abirateron/Prednison ist mit dem der Chemohormontherapie gleichwertig. Aktuell kann nach einer Stellungnahme des Arbeitskreises Onkologie (AKO) und der Arbeitsgemeinschaft urologische Onkologie (AUO) Patienten mit einem hormonsensitiven metastasierten Prostatakarzinom alternativ zur Chemotherapie mit Docetaxel die Kombination aus ADT und Abirateron/Prednison angeboten werden.Die Frage, ob Patienten mit metastasiertem nicht kastrationsresistenten Prostatakarzinom mehr von der Chemohormontherapie oder von der Hormonkombinationstherapie mit Abirateron profitieren, kann zum aktuellen Zeitpunkt nicht abschließend geklärt werden. Aufgrund der besseren Verträglichkeit kann die Kombinationstherapie ADT + Abirateron/Prednison jenen Patienten angeboten werden, die für eine Chemotherapie nicht in Frage kommen. Ökonomisch zu berücksichtigen sind die beträchtlichen Mehrkosten durch höhere Kosten des Präparats und eine längere Therapiedauer.

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“…PCa is a global public issue that threatens human health and life, with increasing morbidity and mortality rates each year (2). Metastatic PCa is commonly treated with androgen deprivation therapy; however, resistance can still develop quickly, which leads to castration-resistant PCa (CRPC) (3). Docetaxel is widely used as the standard first-line chemotherapy treatment for patients with CRPC (3).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of biomarkers and their functions for docetaxel‑resistant prostate cancer cells

Deng

Zeng

et al. 2019

Oncol Lett

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Docetaxel treatment is a standard chemotherapy strategy for castration-resistant prostate cancer (CRPC), and patients with CRPC eventually develop resistance to treatment. However, little is understood regarding the underlying mechanism of resistance. The present study aimed to identify the underlying crucial genes and regulatory networks associated with docetaxel resistance in prostate cancer using bioinformatics analyses. For this purpose, one expression profile dataset (GSE33455), which included two docetaxel-sensitive and two docetaxel-resistant cell lines, was downloaded from the Gene Expression Omnibus database, and analyses of differential gene expression and function enrichment were performed. A protein-protein interaction (PPI) network was constructed, and the associated hub genes were investigated using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape software. A total of 756 differentially expression genes (DEGs) were identified, including 509 downregulated and 247 upregulated genes. Enrichment analysis revealed that the DEGs were associated with the interferon-γ-mediated signaling pathway, protein binding, bicellular tight junctions and cancer pathways. Two modules were screened from the PPI network, and the corresponding genes were identified to be largely enriched in the interferon-γ-mediated signaling pathway and the negative regulators of the DExD/H-Box helicase 58/interferon induced with helicase C domain 1 signaling pathway, and enriched in cell-cell adhesion and the Rap1 signaling pathway. Among the ten hub genes, epidermal growth factor receptor, spleen tyrosine kinase (SYK), intracellular adhesion molecule 1 (ICAM1), interleukin (IL)6, CXC motif chemokine ligand 8 (CXCL8), cyclin dependent kinase 1 and CD44 molecule (CD44) were significantly differentially expressed in prostate cancer tissues compared with healthy tissues based on The Cancer Genome Atlas data. The Gene Expression Profiling Interactive Analysis database revealed that ICAM1 was positively associated with IL6 and CXCL8, and epidermal growth factor receptor was positively associated with CD44 and SYK. Additionally, ten hub genes, which were identified to be associated with the drug resistance of docetaxel in prostatic carcinoma in the present study, were predominantly associated with tumor progression and metastasis. Reverse transcription-quantitative PCR analysis performed on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines demonstrated that certain hub genes, including CDK1, 2′-5′-oligoadenylate synthetase 3, CXCL8 and CDH1, were highly expressed in the docetaxel-resistant cell lines, which confirmed the bioinformatics results. In conclusion, the present study identified a number of important genes that are associated with the molecular mechanism of docetaxel resistance by integrated bioinformatical analysis, and these genes and regulatory networks may assist with identifying potential gene therapy targets for CRPC. Further functional analyses are required to validate the...

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Docetaxel for Metastatic Hormone-sensitive Prostate Cancer: Urgent Need to Minimize the Risk of Neutropenic Fever

Cited by 16 publications

References 10 publications

PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy

PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy

Medikamentöse Tumortherapie des metastasierten nicht kastrationsresistenten Prostatakarzinoms

Identification and characterization of biomarkers and their functions for docetaxel‑resistant prostate cancer cells

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