ABSTRACT
The Hedgehog signaling pathway plays a key role in mammalian embryogenesis, while it is quiescent in adult tissues. The aberrant activation of Hedgehog signaling pathway has been linked to multiple types of malignant tumors, which makes it an attractive target for cancer therapy in recent years. Up to now, two Hedgehog inhibitors (vismodegib and sonidegib) have been proved by FDA for the treatment of tumors. However, drug resistance and severe adverse reactions represent the problems in their clinical application. Novel inhibitors targeting Smo, such as taladegib, NVP-LEQ506, MRT-92, and downstream or upstream of Smo receptor such as Shh ligand and Gli have been developed to overcome the drug resistance and adverse reactions. The current Hedgehog inhibitors are used for treatment of basal cell carcinoma only, while many ongoing clinical trials are conducted to investigate the antitumor effect of Hedgehog inhibitors in other malignancies. Here we reviewed the research progress of the new anticancer drugs targeting the Hedgehog signaling pathway and their prospect in variety of cancers therapy.
ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the antiproliferative activity of 3-(2-chlorophenyl)-1-(2-hydroxy-4, 6-dimethoxy-3-((ethyl(methyl) amino) methyl) phenyl) prop-2-en-1-one (DMF) against human androgen-independent prostate cancer PC3 cells in vitro and its underlying mechanisms.</p><p><b>METHODS</b>The cytotoxic effect of DMF on PC3 cells was measured by MTT assay. Induction of apoptosis was assessed by propidium iodide staining and flow cytometric analysis. Changes of mitochondrial membrane potential (DeltaPsim) were detected by JC-1 staining. The levels of apoptosis related proteins were analyzed by Western blot.</p><p><b>RESULTS</b>DMF exhibited high efficiency on cell growth inhibition in PC3 cells with an IC50 value of (9.5 +/- 0.2)micromol/L. Flow cytometric analysis indicated that DMF could induce apoptosis in PC3 cells. A significant decrease of mitochondrial membrane potential was observed in PC3 cells treated with DMF, which was in a time- and dose-dependent manner. The results of Western blot indicated that DMF induced the activation of caspase-3, increased the ratio of Bax/Bcl-2 and downregulated the expression of phosphate-p38.</p><p><b>CONCLUSION</b>DMF is a potential compound against PC3 cells and the mitochondrial pathway might be involved in DMF-induced apoptosis in PC3 cells.</p>