Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

Abstract

Blocking angiogenesis is a promising approach in cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose chemotherapy, given at short regular intervals with no prolonged breaks (metronomic chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors. ABT-510, a peptide derivative of thrombospondin, kills endothelial cell by increasing CD95L, a ligand for the CD95 death receptor. However, CD95 expression itself is unaffected by ABT-510 and limits its efficacy. We found that multiple chemotherapy agents, cyclophosphamide (cytoxan), cisplatin, and docetaxel, induced endothelial CD95 in vitro and in vivo at low doses that failed to kill endothelial cells (cytoxan > cisplatin > docetaxel). Thus, we concluded that some of these agents might complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining ABT-510 with cytoxan or cisplatin. Cyclophosphamide and cisplatin synergistically increased in vivo endothelial cell apoptosis and angiosuppression by ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model, ABT-510 and cytoxan, applied together at low doses, acted in synergy to delay tumor take, to stabilize the growth of established tumors, and to cause a long-term progression delay of PC-3 prostate carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95, CD95L, and apoptosis. Thus, our study shows a ''complementation'' design of an optimal cancer treatment with the antiangiogenic peptide and a metronomic chemotherapy.Thrombospondin-1 is a well-known antiangiogenic agent (1).Its mechanism of action and structure-function relationship have been analyzed in considerable depth, resulting in the discovery of a minimal active heptapeptide in which antiangiogenic activity is greatly enhanced by L-isoleucine to D-isoleucine replacement (2). ABT-526 and ABT-510 are modified versions of this minimal peptide with increased potencies (3) and improved clearance; ABT-510 is currently under evaluation in phase II clinical trials (4). Thrombospondin-1 has also been identified as a host-derived mediator of the antiangiogenic action of low-dose metronomic chemotherapy (5, 6). Thrombospondin-1 and ABT-510 act by inducing endothelial cell apoptosis in some cases via CD36 cell surface receptor (7,8). Proapoptotic signal elicited by thrombospondin-1 generates CD95L, a ligand for the CD95 death receptor (9). However, CD95 expression on vascular endothelial cell is independent of thrombospondin-1; thus, accessible CD95 limits the rate of apoptosis and antiangiogenesis due to thrombospondin-1 and consequently determines, at least in part, the efficacy of thrombospondin-1-based cancer treatments.Seeking agents to improve the efficacy of ABT-...

Thrombospondin-1 Inhibits Nitric Oxide Signaling via CD36 by Inhibiting Myristic Acid Uptake

“…Similar synergism with cytotoxic agents was also noted for TNP-470 and ABT-510 (63,64). The convergent effects of these two drugs on protein myristoylation may explain these similarities.…”

Inhibition of tumor angiogenesis by oral etoposide

“…therefore, there is an urgent need for multi-drug regimens in treating drug-resistant cancer in the clinic. anti-angiogenic 'metronomic' chemotherapy with cyclophosphamide was shown to be synergistic with the thrombospondin peptide aBt-510 in suppressing tumor growth (43). recent studies show synergy between pparγ ligands, such as rosiglitazone, and platinum-based chemotherapeutic agents in inhibiting tumor growth (44).…”

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

“…Thrombospondin-1 increases the level of Fas ligand on endothelial cells (Volpert et al, 2002;Yap et al, 2005). Moreover, it has been described that SN-38 induces Fas upregulation and caspase 8-mediated apoptosis in multiple myeloma cells (Catley et al, 2004).…”

“…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).…”