Researchers are now able to synthesize indirubin in pure form, including the derivatives indirubin-5-sulfonate and indirubin-3-monoxime. The mechanisms by which indirubin or its derivatives exert their effects against the cancer process are now quite well known. Current research efforts on understanding cancer are focused strongly on signaling processes, or the means by which molecules communicate and are transformed through well-defined pathways leading to cell growth.
Cyclin-dependent kinases
Kinases are enzymes that catalyze the transfer of phosphate groups from one molecule to another. Kinases are essential for normal processes in the body, but their activity is carefully regulated. Kinases are also essential for tumor growth and progression but their activity is unregulated. Inhibitors of the kinase signaling pathways are among the most successful targeted therapies. The cell cycle plays an essential role in cell division, and the cyclin protein appears at various stages in the cycle. Cyclin-dependent kinase must bind to cyclin in order to function.
Indirubin-3-monoxime causes inhibition of cyclin-dependent kinase 1 in human mammary carcinoma cell cultures. This activity prevents cells from completing the cell cycle, which is necessary for cell division. 3
Stat3 activation
The acronym STAT stands for signal transducers and activators of transcription. Signal transducers are essential for cellular function and refer to a series of biochemical reactions that result in cell growth. One family member, Stat3, is particularly important in cancer formation. The Src signaling protein, which resides inside the cell membrane, activates Stat3. 5Src is known as an oncogene, since mutations can result in this protein giving a continuous stimulus to Stat3.
Indirubin derivatives have been found to block Stat3 signaling in human breast and prostate cancer cell lines. One derivative also inhibits Src activity. Viral infection is an important means by which Src becomes activated. The resultant growth inhibition of cancer cells can result in induction of programmed cell death (apoptosis). 4 5
Summary
Indirubin, a compound isolated from a traditional Chinese herbal medicine, is an effective treatment for chronic myelocytic leukemia. Studies have shown that indirubin or its derivatives act by inhibiting excessive signaling of the cyclin-dependent kinases and Stat3 metabolic pathways. The indirubin compounds are effective in cell culture lines of mammary carcinoma, large cell lung carcinoma, and prostate cancer.
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