Antitumor activities of a novel indolin-2-ketone compound, Z24: more potent inhibition on bFGF-induced angiogenesis and bcl-2 over-expressing cancer cells.
The present study was designed to select the effective dosage range of Z24 [3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one], a novel synthetic indolin-2-ketone small-molecule compound, against tumorigenesis and angiogenesis in vitro and in vivo and to investigate the primary action mechanism of Z24 on the angiogenesis by comparing with SU5416 [3-[(2,4-dimethylpyrrol-5-yl)methyllidenyl]-indolin-2-one] in the selective effects on vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF) signaling and Bcl-2-related cell vitality because Z24 is a potential inhibitor of the Bcl-2 that inhibits growth of multiple tumor types in vivo in our previous study. Per os Z24 inhibited dose-dependently the mouse S180 xenograft tumor growth and angiogenesis in mouse subcutaneous (s.c.) Matrigel plugs in vivo. The maximum growth inhibitory rate was 56.1% by 80 mg/kg/day on S180 mouse sarcoma cells; however, the maximum inhibitory potency on angiogenesis in C57BL/6 mouse subcutaneous Matrigel plug model was 50 mg/kg/day. Z24 inhibited angiogenesis in chicken chorioallantoic membrane (CAM) and invasion and inhibited tube formation of endothelial cells in a dose-dependent manner. Compared with SU5416, the IC50 (50% inhibition concentration) of Z24 on the proliferation of ECV-304 carcinoma cells induced by VEGF or bFGF was 24.4 and 17.99 microM, respectively, which is higher or lower, respectively, than that of SU5416 (14.2 microM for VEGF and 22.7 microM for bFGF). Furthermore, the IC50 of Z24 on the proliferation of Bcl-2 over-expressing HeLa cells and non-Bcl-2-expressing (wild-type) HeLa cells are 11.9 and 24.8 microM, respectively. SU5416 did not exert such a selective inhibiting effect on Bcl-2 over-expressing HeLa cells. These results suggest that Z24 per os has dose-dependent antitumor and antiangiogenesis pharmacological activity. The higher selectivity of Z24 on Bcl-2 protein and on bFGF other than VEGF signaling path may contribute to its efficiency against tumor and tumor-associated angiogenesis.
Wang
Li-li
LL
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, PR China. llww621230@yahoo.com
Li
Jin-jun
JJ
Zheng
Zhi-bing
ZB
Liu
Hong-ying
HY
Du
Gang-jun
GJ
Li
Song
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics*
D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; C456900:indolin-2-one; D016222:Fibroblast Growth Factor 2