In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

Abstract

Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/ 100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.

RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

“…The anticancer effect of these drugs when administered episodically at the maximum tolerated dose was attributed to their ability to intercalate DNA and induce topoisomerase II-mediated strand breaks (15). More recently, adriamycin (DXR) has been shown to inhibit tumor xenograft growth through antiangiogenic effects (16,19). However, before our study, the mechanism by which anthracycline chemotherapy impairs tumor angiogenesis had not been established.…”

“…DNR or DXR was injected i.v. on days 28-31 at a dose of 1 mg/kg, which is 5 times lower than the bolus dose of DXR conventionally used to block tumor growth in mice (16). HIF-1-dependent Luc activity was imaged 4 h after treatment on day 30.…”

Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma

“…TSP-1 and ABT-510 act by inducing endothelial cell apoptosis, and recent studies suggest that TSP-1 generates CD95L, a ligand for the CD95 death receptor (37). However, because CD95 expression on the vascular endothelial cell is independent of TSP-1, the efficacy of the drug is limited.…”

Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib

“…Recently, it has been also reported that low doses of cyclophosphamide, cisplatin or docetaxel increase endothelial cell Fas receptor (Quesada et al, 2005;Yap et al, 2005). Thrombospondin-1 increases the level of Fas ligand on endothelial cells (Volpert et al, 2002;Yap et al, 2005).…”