Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery.

Abstract

The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS(2), to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.

• Authors: Hairi Li, Hongyan Zhou, Dong Wang, Jinsong Qiu, Yu Zhou, Xiangqiang Li, Michael G Rosenfeld, Sheng Ding, Xiang-Dong Fu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 12 Pg. 4609-14 (Mar 20 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22396588 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• Antigens
• Antineoplastic Agents
• Cardenolides
• Glycosides
• cannogenin thevetoside
• Proteasome Endopeptidase Complex

Topics

• Androgens (chemistry)
• Antigens (chemistry)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cardenolides (pharmacology)
• Cell Line, Tumor
• Chemistry, Pharmaceutical (methods)
• Drug Design
• Drug Screening Assays, Antitumor (methods)
• Genomics
• Glycosides (chemistry)
• Humans
• Phenotype
• Proteasome Endopeptidase Complex (chemistry)
• RNA Interference