Abstract
Despite that much effort has been made for the development of radiosensitizers, useful drugs are still unavailable in usual clinics of radiotherapy. Antiangiogenic agents are thought to be promising in cancer therapy and many drugs possessing such properties have been developed. Recently, a consensus is being made that the combination of such drugs with radiotherapy is quite effective. Sulfoquinovosylacylglycerol (SQAG) is sulfoglycolipids, which we originally extracted from natural products. We also succeeded in chemical synthesis of the agent. In this study, we show that SQAG could be a unique antiangiogenic radiosensitizer. The agent by itself had an antiangiogenic activity at high doses, however, it synergistically inhibited angiogenesis at low doses when combined with ionizing radiation using different in vitro methods. Combined treatment with SQAG and radiation appears to promote the adoption of a senescence-like phenotype rather than apoptosis by vascular endothelial cells in vitro. The agent remarkably enhanced the radioresponse of several human tumors transplanted into nude mice, accompanied by a significant reduction in the vascularity of the tumors as evaluated by immunohistochemical staining of CD31. Collagen IV, which constitutes the basal membrane of the vessels, was significantly reduced by the combined treatment. The effect of the combined treatment on vascular normalization as evaluated by the time course of α-Sma expression, a marker of pericytes, and hypoxic fractions as determined by pimonidazole staining will also be discussed. We conclude that SQAG could be a potent antiangiogenic radiosensitizer.
