The considerable increase of investment in research and development by the pharmaceutical industry over the past three decades has not added the number of approved new drugs. An important issue ignored by
drug discovery practice is the multi-dimensional interaction network between drugs and their targets. Thus, it is essential to view
drug actions through the lens of network biology. In the current study, based on the co-expression network of
transcription factors and their downstream genes, we proposed a novel approach, called causal co-expression method with module analysis, to screen drugs with specific target and fewer side effects. We presented a causal co-expression method with module analysis and it could be used in analyzing the microarray data of different
drug candidates. At first, the differential wiring value (DW) was calculated to find some causal
transcription factors (TFs) by combining with differential expression genes in the regulated networks. After the discovery of the causal TFs, co-expression module analysis method was applied to mine molecular pharmacology pathways around these causal TFs at molecular level. We applied our methods to two
drug candidates,
Argyrin A and
Bortezomib, both with anti-
cancer activities. We first obtained some differentially expressed
transcription factors of cells treated with
Argyrin A or
Bortezomib. Nearly all these
transcription factors are associated with the
tumor suppressor protein p27kip1. Furthermore, module analysis showed that
Bortezomib inhibited
tumor growth not specifically by cell cycle and cell proliferation pathway, but through many basic metabolic processes which result in cell toxicity. In contrast,
Argyrin A had influence on cell cycle, and was involved in DNA damage repair at the same time, showing that
Argyrin A was a more suitable
drug for anti-
cancer treatment. Our study revealed that the causal co-expression method with module analysis was effective and can be used as a tool to evaluate
drug candidates.