A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin

Abstract

This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor.

Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S

“…However, this discrepancy might be explained by the hormetic response to different concentrations of CD147. Of note, hormetic responses are shared by other anti-angiogenic agents (37,38), and we have demonstrated the hormetic effects of CD147 or its neutralizing antibody in other systems (39, 40). Generally, TIMP-1 is considered an anti-angiogenic factor, because of its ability to inhibit MMPs, MMP-9 in particular.…”

Lithium downregulates phosphorylated acetyl‑CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes

“…In the present study, lithium had a biphasic dose-response effect on ACC2 and GSK-3β activities. This phenomenon may stem from interactions among multiple signaling pathways targeted by lithium (53), resulting in dose-response curves that significantly differ from the monotonic curves typically seen in pharmaceuticals acting on specific receptors (54). Numerous studies have identified the biphasic dose-response effects of lithium on a wide range of signaling pathways in multiple cell types (55)(56)(57)(58).…”

Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

“…Clearly more experiments are needed to clarify the molecular interplay and subsequent casade of events that unfolds during angiogenesis during fracture healing. Another interesting point that has emerged from anti-tumor studies is that endostatin has a biphasic efficacy response (18). In this context, it is tempting to speculate that Bgn could be an upstream “fine-tune” regulator of the many down stream functions that are ascribed to endostatin in pathological situations.…”

“…This observation led us to consider that there were yet unidentified factors that work with Bgn to control vessel formation. Our attention was drawn to endostatin, a 20 kDa C-terminal fragment of type XVIII collagen that has potent antiangiogenic activities (14), and appears to regulate angiogenesis in multiple ways (15–18). Previous work using solid phase binding and immumoprecipitation (IP) showed Bgn directly binds to endostatin (15).…”