Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells.
OBJECTIVE
Inhibition of angiogenesis is an important new treatment modality for malignancies, including gliomas. Vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1alpha (HIF-1alpha) have been investigated as potent mediators of tumor angiogenesis. We investigated whether four major chemotherapeutic agents (ACNU, cisplatin, etoposide, and SN38) showed an angiosuppressive effect in vitro.


METHODS
The effects of ACNU, cisplatin, etoposide, and SN38 for endothelial cells were assessed by cell growth inhibition assay (WST-8 assay) and vessel formation assay (angiogenesis kit). The inhibitory effects of the HIF-1alpha and VEGF expression of glioma cells after SN38 treatment were assessed by real-time RT-PCR, Western blot, and ELISA.


RESULTS
SN38, but not other chemotherapeutic agents, selectively inhibited endothelial cell proliferation and three-dimensional tube formations at the 0.01 microM. Furthermore, SN38 significantly decreased the HIF-1alpha and VEGF expression of glioma cells in a dose- and time-dependent manner under normoxic and hypoxic conditions. SN38 has dual angiosuppressive actions, including both the inhibition of endothelial proliferation and tube formation, and the inhibition of the angiogenic cascade in glioma cells.


CONCLUSIONS
SN38 is an attractive agent as both a direct and indirect angiogenesis inhibitor and provides the anti-glioma agents with an angiosuppressive function.
Kamiyama
Hiroshi
H
Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan.
Takano
Shingo
S
Tsuboi
Koji
K
Matsumura
Akira
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077146:Irinotecan; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000077146:Irinotecan; D002166:Camptothecin