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.
Highlights
prostate cancer (PrCa) is the most diagnosed and third most deadly cancer among men in Western industrialized nations [1]
We identified gambogic acid (GA) among several traditional Chinese medicines as a potent therapeutic for inhibiting the proliferation of aggressive prostate cancer
GA was active in a variety of heterogeneous and clinically-relevant castrate resistant prostate cancer (CRPC) models, assayed in 3D organoid cultures
Summary
PrCa is the most diagnosed and third most deadly cancer among men in Western industrialized nations [1]. Most prostate cancer-related deaths are attributable to metastatic spread. Metastatic PrCa is treated with androgen deprivation therapy (ADT) because most prostate cancers require androgen receptor (AR) signaling to maintain growth and viability. Almost all men with metastatic PrCa develop resistance to ADT, referred to as metastatic castrate-resistant prostate cancer (mCRPC) [2, 3]. Acquired resistance to ADT is mainly the consequence of genetic alterations to components of the AR signaling pathway that restore activity even with castrate levels of androgens [4, 5]. Following the development of resistance to AR pathway inhibitors, relatively few treatments currently exist. There is a need for additional therapeutic approaches to deter mCRPC progression
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