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KMID : 0043320090320060915
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Archives of Pharmacal Research
2009 Volume.32 No. 6 p.915 ~ p.922
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Anti-tumor Activity of Noble Indirubin Derivatives in Human Solid Tumor Models In Vitro
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Kuh Hyo-jeong
Kim Yong-Chul
Choi Soo-Jeong
Kim Soo-Hyun
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Abstract
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Indirubin has been identified as a component of a traditional Chinese medicine, Danggui Longhui Wan, which is used for the treatment of chronic myelogenous leukemia. Indirubin inhibits cyclin-dependent kinases (CDKs) and induces cell cycle arrest and apoptosis in cancer cells. Many indirubin derivatives have been studied for their potential anti-solid tumor activity. We have synthesized and evaluated many indirubin derivatives. In order to compare and confirm the potential of our major derivatives as anti-solid tumor agents, we examined their anti-proliferative activity in monolayers, as well as in multicellular spheroids (MCS) cultures of human colorectal cancer cells, DLD-1 and HT-29. The MCS model is an in vitro solid tumor model that is increasingly used for the evaluation of anti-solid tumor activity. 5-nitro-indirubin- 3’-oxime (4c) and 5’-bromo-5-nitro-indirubin-3’-oxime (4l), compared to 5-trimethylacetamido-indirubin-3’-oxime (11) and 5-diphenylacetamido-indirubin-3’-oxime (33) showed greater anti-proliferative effects in monolayers, but lower anti-proliferative effects in MCS. Overall, our data suggest that compounds 11 and 33 may exert a significant anti-solid tumor activity via a mechanism other than CDK inhibition, different from that of 4c and 4l. These compounds are worth further investigation with respect to their anti-solid tumor activity and their mechanism of action in various solid tumor models.
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KEYWORD
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Indirubin derivatives, Multicellular spheroids (MCS), Antitumor activity, Colon cancer, In vitro
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