Oncotarget

Research Papers:

Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer

Hong Pan, Keith H. Jansson, Michael L. Beshiri, JuanJuan Yin, Lei Fang, Supreet Agarwal, Holly Nguyen, Eva Corey, Ying Zhang, Jie Liu, HuiTing Fan, HongSheng Lin and Kathleen Kelly _

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Oncotarget. 2017; 8:77181-77194. https://doi.org/10.18632/oncotarget.20424

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Abstract

Hong Pan1,2,3, Keith H. Jansson3, Michael L. Beshiri3, JuanJuan Yin3, Lei Fang3, Supreet Agarwal3, Holly Nguyen4, Eva Corey4, Ying Zhang1, Jie Liu1, HuiTing Fan1, HongSheng Lin1 and Kathleen Kelly3

1Laboratory of Cancer, Guang’anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing, China

2Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China

3Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

4Department of Urology, University of Washington, Seattle, Washington, USA

Correspondence to:

Kathleen Kelly, email: [email protected]

HongSheng Lin, email: [email protected]

Keywords: gambogic acid, CRPC, ROS, thioredoxin, organoids

Received: April 26, 2017    Accepted: June 26, 2017    Published: August 24, 2017

ABSTRACT

Advanced prostate cancer (PrCa) is treated with androgen deprivation therapy, and although there is usually a significant initial response, recurrence arises as castrate resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with combined homozygous alterations to PTEN and TP53 comprise about 30% of clinical samples. We screened eleven traditional Chinese medicines against a panel of androgen-independent Pten/Tp53 null PrCa-derived cell lines and identified gambogic acid (GA) as a highly potent growth inhibitor. Mechanistic analyses revealed that GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death. Consistent with this, we determined that GA inhibited thioredoxin, a necessary component of cellular anti-oxidative, protein-reducing activity. In other clinically relevant models, GA displayed submicromolar, growth inhibitory activity against a number of genomically-representative, CRPC patient derived xenograft organoid cultures. Inhibition of ROS with N-acetyl-cysteine partially reversed growth inhibition in CRPC organoids, demonstrating ROS imbalance and implying that GA may have additional mechanisms of action. These data suggest that redox imbalances initiated by GA may be useful, especially in combination therapies, for treating the heterogeneity and plasticity that contributes to the therapeutic resistance of CRPC.


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