They identified Seliciclib structure aldehydehehydrogenase (ALDH) positive and CD133+ colorectal CSC using flow cytometry. The demonstrated that isolated CSC exhibited STAT-3 (signal transducers and activators of transcription-3) activation and treated them with GO-Y030. GO-Y030 inhibited STAT3 phosphorylation and reduced STAT3 downstream target gene expression
resulting in induction of apoptosis in colon CSC. Additionally, GO-Y030 suppressed tumor and CSC growth of SW480 and HCT-116 colon cancer cell lines in vivo in mouse models. Interestingly, Curcumin has been shown to also inhibit cell growth and apoptosis in pancreatic cancer cells. Its effect was associated with down-regulation of Notch-1 expression, which suggests that Curcumin may be associated with potential advantageous activity against pathways that are upregulated in CSC[18]. Other attempts to target Notch signaling in gastrointestinal CSC have, however, not been very successful. Gamma-secretase inhibitors (GSI) are thought to antagonize Notch signaling through blocking of Notch receptor cleavage[69].
Evaluation of the effect of GSI in two gastric cancer cell lines did not result in any appreciable anti-tumor effects[70]. These results were surprising since GSI have shown promising antitumor potential in leukemia, breast and glioblastoma multiformes models[71-73]. Evolving evidence suggests that targeting the Hedgehog pathway may be a feasible strategy to inhibit CSC. Cyclopamine, a naturally occurring hedgehog
inhibitor has shown promising potential[46]. As a single agent cyclopamine suppressed the invasion of pancreatic cancer cells[4]. Cyclopamine reduced the percentage of cells expressing the pancreatic CSC markers such as ALDH[74]. In combination with gemcitabine, cyclopamine resulted in reduction of metastasis in an orthotopic xenograft model[74]. To further clarify this observation, Yao et al[74] demonstrated that cyclopamine dowregulated the expression of CD44 and CD133+ in gemcitabine-resistant pancreatic cancer cells indicating that it may be an effective modality for reversing gemcitabine resistance in pancreatic CSC. A similar observation was made Dacomitinib in gastric CSC where blocking of Hedgehog pathway with cyclopamine decreased self-renewing properties and enhanced sensitivity of gastric cancer cells to chemotherapeutic agents[75]. Additionally, Feldmann et al[76] demonstrated that IPI-269609, a novel Hedgehog inhibitor, inhibited growth and metastasis of pancreatic cancer mostly through targeting of the CSC. Since the Wnt pathway is also deregulated in CSC, it represents an intriguing target for cancer treatment. Anti-Wnt therapy is in early stages of clinical development[77]. He et al[77] demonstrated that a monoclonal antibody against Wnt-1 induced apoptosis in human cancer cells. Also, Salinomycin, an antibiotic commonly used in poultry firmly, is thought to suppress Wnt/β-catenin signal transduction[78].