A novel hypoxia-dependent 2-nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors

Abstract

Tumour angiogenesis is initiated by angiogenic factors that are produced in large amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour-specific antiangiogenesis because normal tissues are not usually hypoxic. On the other hand, blocking a biological function of endothelial cells is known to result in angiogenic inhibition. To produce a tumour-specific and powerful antiangiogenesis, we determined whether potent angiogenic inhibition could be achieved by inhibiting the production of angiogenic factors by hypoxic tumour cells and simultaneously blocking certain angiogenic steps in endothelial cells under normoxia. We focused on the 2-nitroimidazole moiety, which is easily incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic cytotoxin. We designed and synthesised 2-nitroimidazole derivatives designated as KIN compounds, and investigated their antiangiogenic activities under normoxia using a chick embryo chorioallantoic membrane. KIN-841 (2-nitroimidazole 1-acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent manner. This compound inhibited the proliferation of bovine pulmonary arterial endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation by KIN-841 under hypoxia increased about five-fold compared to that under normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive production of vascular endothelial cell growth factors induced by 3LL cells as determined by tritium-labelled thymidine ([ 3 H]thymidine) incorporation into BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL-cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These results indicate that the regulation of the production of angiogenic factors by hypoxic tumour cells is a useful target for tumour-specific angiogenesis inhibition, and that KIN-841, which causes simultaneous direct inhibition of endothelial cell function and production of angiogenic factors by hypoxic tumour cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the potential for clinical use of KIN-841 as an antitumour drug is very high.

Antitumor effects of 2‐oxoglutarate through inhibition of angiogenesis in a murine tumor model

“…Tumor‐induced blood vessel formation was assessed as described previously. ( 23 ) In brief, Millipore chambers (Millipore) were filled with either PBS alone or a suspension of 1.5 × 10 7 LLC cells in PBS with or without 2‐OX and sealed with membrane filters (0.45‐µm pores). Chambers were implanted subcutaneously in dorsal air sacs created surgically by injection of an appropriate volume of air in 7‐week‐old male C57BL/6J mice.…”

Exploring Unique Structures: Flexibility is a Significant Factor in Biological Activity

“…[57][58][59] In this section, molecular design and synthesis of several 2-nitroimidazole analogs are reported. [60][61][62][63][64][65][66][67][68] Haloacetylcarbamoyl-2-nitroimidazole analogs have a chiral center, and show antiangiogenetic activity. 8) Methyl including TXs, TX-1863, -1878, -1866, -1879, inhibited angiogenesis (80-100%) at 100 mg/pellet (Fig.…”

Concept, mechanisms and therapeutics of angiogenesis in cancer and other diseases

“…Selective delivery of this drug into the tumour neovascular endothelium may dissociate the desired anti-angiogenic effects from the immunosuppressive effects that unfavourably affect tumour growth (Guba et al 2002). In another study, an attempt was made to inhibit the production of angiogenic factors in hypoxic tumour cells using a novel hypoxia-dependent 2-nitroimidazole, KIN-841, which covalently binds and is cytotoxic to hypoxic tumour cells, and simultaneously disrupt the endothelial cell function using the same agent, to achieve angiogenesis inhibition (Shimamura et al 2003). It was observed that KIN-841 inhibited the proliferation of endothelial cells under normoxia.…”