Abstract
Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells. Here we show that the protein arginine methyl transferase (PRMT) type 1 inhibitor, MS023, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Differentiation changes in the highly aggressive human colon cancer cell line (HT-29) were proved by proteomic and genomic approaches. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes. These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation.
Highlights
Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells
Two colon cancer cell lines HT-29 and HCT-116, and a normal colon epithelial cell line CCD-841 were tested for basal alkaline phosphatase (ALP) activity
HT-29 was considered as a suitable candidate for the High Throughput Screening (HTS) screening, and SB can be used as a positive control for phenotypic modulation. 5790 compounds from different chemical libraries, including 30 compounds from The Structural Genomics Consortium (SGC) Epigenetic Chemical Probe Collection, were screened at 10 μM concentration for their ability to induce ALP activity and delay growth of HT-29 cells (Z′ > 0.4)
Summary
Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation. A panel of 33 colon cancer cells lines were screened for differentiation effect of H DACi25 by measurement of ALP activity following treatment. We recently developed a new multiplex assay applicable for HTS, where ALP activity can be measured and normalized per live cell number in the same well—CDP/CTG a ssay[29] This method allows a rapid screening of compounds, which can induce differentiation of responsive colon cancer cells, using affordable and commercially available reagents. We performed a phenotypic HTS screen in HT-29 cells and discovered PRMT type 1 inhibitor, MS023, as a potent inducer of ALP activity promoting cell differentiation phenotype
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