Estramustine Phosphate Inhibits TGF-β-Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production

Transforming growth factor-beta (TGF-β) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF-β regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF-β-induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-β. Moreover, EP greatly reduced the capacity of TGF-β to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF-β-induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-β.

Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: A single-center study.

e542 Background: The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) for high-risk Pca patients treated with neoadjuvant therapy comprising a luteinizing hormone-releasing hormone agonist plus low-dose estramustine (LHRH agonist + EMP) prior to radical prostatectomy (RP). In the present study, we evaluated the efficacy of neoadjuvant therapy comprising a gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate (GnRH antagonist + EMP) in patients with high-risk Pca. Methods: Between September 2005 and March 2016, we identified 406 high-risk Pca patients of whom 136 received neoadjuvant GnRH antagonist + EMP and 270 received LHRH agonist + EMP before RP. We retrospectively evaluated the clinical and pathological covariates between the two groups. The primary endpoint was the rate of pathological ≤ T2 status, and the secondary endpoint was BRFS. Results: The rates of pathological ≤ T2 status were 80.2% and 61.5% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P < 0.001). The 3-year BRFS rates were 97.8% and 85.2% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P = 0.021). Multivariate analysis revealed that biopsy Gleason score, GnRH antagonist + EMP, and clinical T stage were independent predictors of pathological ≤ T2 status in surgical specimens. Conclusions: Our findings suggest that neoadjuvant GnRH antagonist + EMP followed by RP may improve the pathological outcomes and reduce the risk of biochemical recurrence in patients with high-risk Pca. Further prospective studies to confirm these findings are warranted.