scholarly journals Reovirus mutant jin-3 exhibits lytic and immune-stimulatory effects in preclinical human prostate cancer models

Author(s):  
Arjanneke F. van de Merbel ◽  
Geertje van der Horst ◽  
Maaike H. van der Mark ◽  
Selas T. F. Bots ◽  
Diana J. M. van den Wollenberg ◽  
...  

AbstractTreatment of castration-resistant prostate cancer remains a challenging clinical problem. Despite the promising effects of immunotherapy in other solid cancers, prostate cancer has remained largely unresponsive. Oncolytic viruses represent a promising therapeutic avenue, as oncolytic virus treatment combines tumour cell lysis with activation of the immune system and mounting of effective anti-tumour responses. Mammalian Orthoreoviruses are non-pathogenic human viruses with a preference of lytic replication in human tumour cells. In this study, we evaluated the oncolytic efficacy of the bioselected oncolytic reovirus mutant jin-3 in multiple human prostate cancer models. The jin-3 reovirus displayed efficient infection, replication, and anti-cancer responses in 2D and 3D prostate cancer models, as well as in ex vivo cultured human tumour slices. In addition, the jin-3 reovirus markedly reduced the viability and growth of human cancer cell lines and patient-derived xenografts. The infection induced the expression of mediators of immunogenic cell death, interferon-stimulated genes, and inflammatory cytokines. Taken together, our data demonstrate that the reovirus mutant jin-3 displays tumour tropism, and induces potent oncolytic and immunomodulatory responses in human prostate cancer models. Therefore, jin-3 reovirus represents an attractive candidate for further development as oncolytic agent for treatment of patients with aggressive localised or advanced prostate cancer.

2009 ◽  
Vol 62 (5) ◽  
pp. 1112-1119 ◽  
Author(s):  
H. Carl Le ◽  
Mihaela Lupu ◽  
Khushali Kotedia ◽  
Neal Rosen ◽  
David Solit ◽  
...  

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Kai Li ◽  
Qiusheng Zheng ◽  
Xiaoyu Chen ◽  
Yunchao Wang ◽  
Dan Wang ◽  
...  

Prostate carcinoma causes a great number of deaths every year; therefore, there is an urgent need to find new drug candidates to treat advanced prostate cancer. Isobavachalcone (IBC) is the chalcone composition of Psoralea corylifolia Linn used in traditional Chinese medicine. Although IBC demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of IBC have not been fully defined. In our study, we found that IBC may induce reactive oxygen species- (ROS-) mediated apoptosis via interaction with a selenocysteine (Sec) containing the antioxidant enzyme thioredoxin reductase 1 (TrxR1), and induce lethal endoplasmic reticulum (ER) stress by inhibiting TrxR1 activity and increasing ROS levels in human prostate cancer PC-3 cells. Furthermore, we also observed that knocking down TrxR1 would sensitized cancer cells to IBC treatment. Our study provides evidence for the anticancer mechanism of IBC with TrxR1 as a potential target.


Medicines ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 28
Author(s):  
Mohamed Ben-Eltriki ◽  
Subrata Deb ◽  
Gehana Shankar ◽  
Gray Meckling ◽  
Mohamed Hassona ◽  
...  

In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using nuclear receptor signaling. Athymic male nude mice were utilized to establish an androgen-independent human prostate cancer C4-2 cell castration-resistant prostate cancer (CRPC) xenograft model. Mice were treated orally for six weeks with 70 mg/kg aPPD administered once daily or three times per week with 4 µg/kg calcitriol or in combination or only with vehicle control. Contrary to our expectations, calcitriol treatment alone increased C4-2 tumor growth. However, the addition of calcitriol substantially increased aPPD-mediated tumor growth suppression (76% vs. 53%, combination vs. aPPD alone). The combination treatment significantly increased levels of cleaved caspase-3 apoptotic marker compared to vehicle-treated or aPPD-treated C4-2 tumors. The mechanistic elucidations indicate that tumor inhibition by the aPPD and calcitriol combination was accompanied by elevated vitamin D receptor (VDR) protein expression. In silico data suggest that aPPD weakly binds to the native LBD pocket of VDR. Interestingly, the combination of aPPD and calcitriol activated VDR at a significantly higher level than calcitriol alone and this indicates that aPPD may be an allosteric activator of VDR. Overall, aPPD and calcitriol combination significantly inhibited tumor growth in vivo with no acute or chronic toxic effects in the C4-2 xenograft CRPC nude mice. The involvement of VDR and downstream apoptotic pathways are potential mechanistic routes of antitumor effects of this combination.


The Prostate ◽  
2002 ◽  
Vol 52 (1) ◽  
pp. 20-33 ◽  
Author(s):  
Eva Corey ◽  
Janna E. Quinn ◽  
Franck Bladou ◽  
Lisha G. Brown ◽  
Martine P. Roudier ◽  
...  

The Prostate ◽  
2004 ◽  
Vol 59 (1) ◽  
pp. 22-32 ◽  
Author(s):  
Emily S. Van Laar ◽  
Steven Weitman ◽  
John R. MacDonald ◽  
Stephen J. Waters

2016 ◽  
Vol 36 (10) ◽  
pp. 5079-5086 ◽  
Author(s):  
RAJU CHELLURI ◽  
TIFFANY CAZA ◽  
MARK R WOODFORD ◽  
JAY E REEDER ◽  
GENNADY BRATSLAVSKY ◽  
...  

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