Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer

Abstract

In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent. [Mol Cancer Ther 2007;6(5):1509 -16]

The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells

“…The results of our in vitro study indicated that expression of MAPT protein isoforms less than 70 KDa had the most influence on sensitivity to taxanes. A discrepancy between MAPT mRNA expression and protein expression has been found previously [37], and thus analysis of MAPT mRNA expression may not be appropriate for examining the utility of MAPT as a predictor of taxane sensitivity. Furthermore, the status of the expression of different MAPT protein isoforms is important in determining sensitivity to taxanes, but immunohistochemistry cannot be used to evaluate each isoform.…”

Tau and Tauopathies

“…Tau expression has been reported in muscle, liver, kidney, and other tissues 40; 41 . It has also been found in human breast, prostate, gastric, and pancreatic cancer cell lines and tissues 42; 43; 44; 45; 46 , as well as in the muscle cells of individuals with inclusion body myositis 47 . The function of tau in non-neuronal cells remains to be elucidated and functions outside of the cytoskeleton may have significance for neurodegenerative disease.…”

Tau in Tauopathies That Leads to Cognitive Disorders and in Cancer

“…Tau expression has also been noticed in different non-neuronal cells like those of the liver, kidney, muscle and so on [126,127] Tau protein has also been expressed in human breast, prostate, gastric and pancreatic cancer cell lines and tissues [12][13][14][15][16]. Tau is also found in patients with twisted tubulofilaments of inclusion-body myositis [19].…”

“…In addition to neurons, tau expression has been noticed in human breast, prostate, gastric, colorectal and pancreatic cancer cell lines and tissues [12][13][14][15][16][17][18]. Tau is also found in patients with twisted tubulofilamentous of inclusion-body myositis [19].…”