Small molecule selectively suppresses MYC transcription in cancer cells.

Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in down-regulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYC-dependent tumors.

The synthetic molecule stauprimide impairs cell growth and migration in triple-negative breast cancer.

Stauprimide, a semi-synthetic derivative of staurosporine, is known mainly for its potent differentiation-enhancing properties in embryonic stem cells. Here, we studied the effects of stauprimide in cell growth and migration of triple-negative breast cancer cells in vitro, evaluating its potential antitumoral activity in an orthotopic mouse model of breast cancer in vivo. Our results from survival curves, EdU incorporation, cell cycle analysis and annexin-V detection in MDA-MB-231 cells indicated that stauprimide inhibited cell proliferation, arresting cell cycle in G2/M without induction of apoptosis. A decrease in the migratory capability of MDA-MB-231 was also assessed in response to stauprimide. In this work we pointed to a mechanism of action of stauprimide involving the modulation of ERK1/2, Akt and p38 MAPK signalling pathways, and the downregulation of MYC in MDA-MB-231 cells. In addition, orthotopic MDA-MB-231 xenograft and 4T1 syngeneic models suggested an effect of stauprimide in vivo, increasing the necrotic core of tumors and reducing metastasis in lung and liver of mice. Together, our results point to the promising role of stauprimide as a putative therapeutic agent in triple-negative breast cancer.

Stauprimide Priming of Human Embryonic Stem Cells toward Definitive Endoderm.

OBJECTIVE: In vitro production of a definitive endoderm (DE) is an important issue in stem cell-related differentiation studies and it can assist with the production of more efficient endoderm derivatives for therapeutic applications. Despite tremendous progress in DE differentiation of human embryonic stem cells (hESCs), researchers have yet to discover universal, efficient and cost-effective protocols. MATERIALS AND METHODS: In this experimental study, we have treated hESCs with 200 nM of Stauprimide (Spd) for one day followed by activin A (50 ng/ml; A50) for the next three days (Spd-A50). In the positive control group, hESCs were treated with Wnt3a (25 ng/ml) and activin A (100 ng/ml) for the first day followed by activin A for the next three days (100 ng/ml; W/A100-A100). RESULTS: Gene expression analysis showed up regulation of DE-specific marker genes (SOX17, FOXA2 and CXCR4) comparable to that observed in the positive control group. Expression of the other lineage specific markers did not significantly change (p<0.05). We also obtained the same gene expression results using another hESC line. The use of higher concentrations of Spd (400 and 800 nM) in the Spd-A50 protocol caused an increase in the expression SOX17 as well as a dramatic increase in mortality rate of the hESCs. A lower concentration of activin A (25 ng/ml) was not able to up regulate the DE-specific marker genes. Then, A50 was replaced by inducers of definitive endoderm; IDE1/2 (IDE1 and IDE2), two previously reported small molecule (SM) inducers of DE, in our protocol (Spd-IDE1/2). This replacement resulted in the up regulation of visceral endoderm (VE) marker (SOX7) but not DE-specific markers. Therefore, while the Spd-A50 protocol led to DE production, we have shown that IDE1/2 could not fully replace activin A in DE induction of hESCs. CONCLUSION: These findings can assist with the design of more efficient chemically-defined protocols for DE induction of hESCs and lead to a better understanding of the different signaling networks that are involved in DE differentiation of hESCs.