Antitumor activity of novel indirubin derivatives in rat tumor model.
OBJECTIVE
The novel indirubin derivatives 5'-nitro-indirubinoxime, 5'-fluoro-indirubinoxime, and 5'-trimethylacetamino-indirubinoxime were designed and tested for antitumor activity both in vitro and in vivo using rat tumor model.


METHODS
Three-week-old male Sprague-Dawley rats were inoculated s.c. on the left flank with 10(7) RK3E-ras rat kidney epithelial cells harboring k-ras gene. Alternatively, 5 x 10(6) RK3E-ras cells were injected into the oral mucosa. Indirubin derivative treatment began on the 3rd or 6th day after oral or s.c. cell injection, respectively. Indirubin derivatives were directly injected into the tumor every other day for a total of five times. Animals were monitored daily and tumor volume was measured by caliper.


RESULTS
Indirubin derivatives showed potent antiproliferative activity on various human cancer cells and oncogenic RK3E-ras rat kidney cells, with IC(50) ranging from 1 to 12 mumol/L. Treatment with indirubin derivatives induced the activation of caspase-7 followed by apoptosis in RK3E-ras cells. Indirubin derivatives showed strong antitumor activity in rat solid and oral tumor models. Direct injection of indirubin derivatives every other day for 10 days induced significant inhibition of tumor growth in Sprague-Dawley rats bearing RK3E-ras-induced tumors. Histologically, treatment with indirubin derivatives caused significant inhibition of tumor formation with increased apoptosis and decreased tumor cell proliferation.


CONCLUSIONS
Our data showed that novel indirubin derivatives 5'-nitro-indirubinoxime, 5'-fluoro-indirubinoxime, and 5'-trimethylacetamino-indirubinoxime effectively arrested the tumor growth by inhibiting cell proliferation and inducing apoptosis. These findings provide the potential value of indirubin derivatives as novel candidates for antitumor agents.
Kim
Soo-A
SA
Department of Biochemistry, Dongguk University College of Oriental Medicine, Kyungju, South Korea.
Kim
Yong-Chul
YC
Kim
Si-Wouk
SW
Lee
Sang-Ho
SH
Min
Jung-Joon
JJ
Ahn
Sang-Gun
SG
Yoon
Jung-Hoon
JH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007211:Indoles; D053148:Caspase 3; C027185:indirubin