Hayat Albtoush, Shaihana Almatrrouk, Thomas Walker, Anthony Oliver, Ian Hampson, Sally Freeman and Lynne Hampson
Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom
Background: Contact inhibition is a key anti-cancer mechanism that arrests cell division when cells reach a high density. This tumour suppressive mechanism triggers many anti-proliferative/growth control signals. Among these signals is the Hippo/YAP pathway. Dysregulation of this pathway plays a major role in the development of cancer, most notably liver cancer. Based on the structure of the Rho A kinase (ROCK) inhibitor Y27632 four structural analogues (YA1-YA4) have been found to induce cell contact growth inhibition of Ras transformed murine NIH3T3 cells. This effect was persistent, non-cytotoxic and only observed when the transformed cells were co-cultured with non-transformed NIH3T3 cells.
Objectives: To synthesis new analogues of Y27632. To evaluate their ability to induce cell contact growth inhibition in human hepatocytes cells transformed by ectopic expression of hepatitis C virus NS4B and Core proteins. To investigate the mode of action of these compounds.
Results and Discussion: Amide coupling methods were used to synthesise structural analogues of Y27632. Cell culture, Human Transcriptome Microarray, and immunohistochemistry were used to probe the mode of action of these compounds.YA1 induced persistent cell contact growth inhibition in co-culture of transformed and non-transformed human hepatocytes. YA1 also significantly activated the HIPPO pathway but no effect of YA1 was observed on the expression of the YAP protein. The Hippo pathway is a promising target for non-cytotoxic cancer therapy and work is in progress to investigate the effect of the other analogues.
Keywords: Cancer, Hippo signaling pathway, ROCK inhibitor.