Abstract
Indirubin is an active component of the herbal ingredient ‘Danggui Longhui wan’, which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs) in interference with AMPK and LKB1, the cellular metabolic sensors. In this study, we screened the effect of meisoindigo on a panel of 300 protein kinases and found that it selectively inhibited Stat3-associated tyrosine kinases and further confirmed its activity in cell based assays. To gain a deeper insight into the structure–activity relationship we produced 7 bromo-derivatives exhausting the accessible positions on the bisindole backbone except for in the 4-position due to the space limitation. We compared their anti-proliferative effects on tumor cells. We found that 6-bromomeisoindigo showed improved toxicity in company with increased Stat3 inhibition. Moreover, we detected that 6-bromomeisoindigo induced apoptosis of 95% of CD133+ pancreatic cancer cells. Considering that CD133 is a common marker highly expressed in a range of CSCs, our results imply the potential application of 6-bromomeisoindigo for the treatment of CSCs in different types of cancers.
Highlights
Indigo, a natural 2,20 -bisindole, is one of the most successful natural pigments with an annual consumption of several thousand tons (Figure 1) [1]
We performed protein kinase profiling using a panel of 300 protein kinases and found that meisoindigo selectively inhibited tyrosine kinases related to Stat3 activity kinases and found that meisoindigo selectively inhibited tyrosine kinases related to Stat3 activity in in vitro as well as in vivo, confirmed by cell-based assays
We identified that meisoindigo and 6-bromo-meisoindigo are potent Stat3 inhibitors and kill CD133+ cancer stem cells (CSCs) in tumors
Summary
A natural 2,20 -bisindole, is one of the most successful natural pigments with an annual consumption of several thousand tons (Figure 1) [1]. This cell line derived from a male patient suffering from pancreatic ductal adenocarcinoma [15] This cell line contains a large population of cancer stem cells (CSCs) expressing stem cell markers CD133 [16,17]. In vitro and in vivo studies showed that indirubin derivatives are potent Src family kinases (SFKs). Active Stat has been found in various tumor types and tissues including leukemias [30], cervical [31], colorectal [32], and pancreatic cancer [33], which contributes to including leukemias [30], cervical [31], colorectal [32], and pancreatic cancer [33], which contributes to tumor initiation, progression, invasion, migration, and formation of metastases [34,35]. Embryonic stem cells and pancreatic CSCs [36,37]
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