“The 14th In Silico Megabank Research Seminar” will be held on Friday, October 12.

・Date/Time: October 12 (Fri.) 15:00‐16:00
・Venue: Conference Room 1 (2F), Tohoku Medical Megabank Organization
・Title: How promoters help to find new drugs Mechanisms of action of RITA compound on cancer cells
・Lecturer: Dr. Olga Kel (Director Applied Life Science Informatics geneXplain GmbH)

・Abstract:
The current study is done in collaboration between Karolinska Institute, Sweden, Institute of Biomedical Chemistry, Russia, and geneXplain GmbH, Germany, and partially funded by European commission in FP7 research project “Net2Drug”.

Background. Antineoplastic compound RITA is known to prevent p53-mdm2 interactions and thus to result in increasing levels of active p53.

High concentrations of RITA cause apoptosis in cancer cells, however small concentrations of RITA do not.

Aim of the study. To understand concentration- and time-dependent molecular  mechanisms of action of the antineoplastic compound RITA as well as to suggest novel candidate compounds to be applied in combination with small concentration of RITA, the following steps were done.

Initially, large scale gene expression and ChIP-seq studies were performed on breast cancer MCM7 cells treated with RITA in both high and small concentration.

At the next step, computational analysis with the geneXplain platform confirmed concentration- and time-dependent downregulation of pro-survival genes. Upstream analysis approach was applied to these genes. First, their promoters were analyzed and combinations of transcription factors involved in their regulation were identified. Next, topological modeling of the signal transduction network upstream of these transcription factors revealed potential master-regulators of the cell survival program that may prevent efficient apoptosis in cancer cells. We considered master regulatory proteins (e.g. PI3K subunits) as causal biomarkers as well as prospective targets for novel anticancer drug combinations.

Then, the cheminformatics program PASS was applied to the target molecules suggest at the previous step. We identified several novel prospective antineoplastic chemical compounds.

Finally, two compounds were experimentally validated in a cellular assay confirming their potential to selectively triggering apoptosis in cancer cells and act synergistically with small concentration of RITA.