Imaging assisted evaluation of antitumor efficacy of a new histone deacetylase inhibitor in the castration-resistant prostate cancer.

Abstract

PURPOSE:

Castration-resistant prostate cancer (CRPC) is the most common cause of death in men. The effectiveness of HDAC inhibitors has been demonstrated by preclinical models, but not in clinical studies, probably due to the ineffectively accumulation of HDACI in prostate cancer cells. The purpose of this work was to evaluate effects of a novel HDACI (CN133) on CRPC xenograft model and 22Rv1 cells, and develops methods, PET/CT imaging, to detect the therapeutic effects of CN133 on this cancer.

METHODS:

We designed and performed study to compare the effects of CN133 with SAHA on the 22Rv1 xenograft model and 22Rv1 cells. Using PET/CT imaging with [11C] Martinostat and [18F] FDG, we imaged mice bearing 22Rv1 xenografts before and after 21-day treatment with placebo and CN133 (1 mg/kg), and uptake on pre-treatment and post-treatment imaging was measured. The anti-tumor mechanisms of CN133 were investigated by qPCR, western blot, and ChIP-qPCR.

RESULTS:

Our data showed that the CN133 treatment led to a 50% reduction of tumor volume compared to the placebo that was more efficacious than SAHA treatment in this preclinical model. [11C] Martinostat PET imaging could identify early lesions of prostate cancer and can also be used to monitor the therapeutic effect of CN133 in CRPC. Using pharmacological approaches, we demonstrated that effects of CN133 showed almost 100-fold efficacy than SAHA treatment in the experiment of cell proliferation, invasion, and migration. The anti-tumor mechanisms of CN133 were due to the inhibition of AR signaling pathway activity by decreased HDAC 2 and 3 protein expressions.

CONCLUSION:

Taken together, these studies provide not only a novel epigenetic approach for prostate cancer therapy but also offering a potential tool, [11C] Martinostat PET/CT imaging, to detect the early phase of prostate cancer and monitor therapeutic effect of CN133. These results will likely lead to human trials in the future.

• Authors: Zude Chen, Xiashuang Wang, Xiaoshuang Yang, Yulong Xu, Yu Yang, Hao Wang, Tao Li, Ping Bai, Gengyang Yuan, Huabiao Chen, Jing Yang, Stephanie A Fiedler, Robin Striar, Daniela R Bernales, Robert E Koegel, Qi Cao, Chongzhao Ran, Bo Xiang, Hong Li, Changning Wang
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 48 Issue 1 Pg. 53-66 (01 2021) ISSN: 1619-7089 [Electronic] Germany
• PMID: 32592040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Male
• Mice
• Positron Emission Tomography Computed Tomography
• Prostatic Neoplasms, Castration-Resistant (diagnostic imaging, drug therapy)
• Xenograft Model Antitumor Assays