CTA095, a novel Etk and Src dual inhibitor, induces apoptosis in prostate cancer cells and overcomes resistance to Src inhibitors.

Abstract

Etk is a non-receptor tyrosine kinase, which provides a strong survival signal in human prostate cancer cells. Src, another tyrosine kinase that cross-activates with Etk, has been shown to play an important role in prostate cancer metastasis. Herein, we discovered a new class of Etk inhibitors. Within those inhibitors, CTA095 was identified as a potent Etk and Src dual inhibitor. CTA095 was found to induce autophagy as well as apoptosis in human prostate cancer cells. In addition, CTA095 inhibited HUVEC cell tube formation and "wound healing" of human prostate cancer cells, implying its role in inhibition of angiogenesis and metastasis of human prostate cancer. More interestingly, CTA095 could overcome Src inhibitor resistance in prostate cancer cells. It induces apoptosis in Src inhibitor resistant prostate cancer cells, likely through a mechanism of down regulation of Myc and BCL2. This finding indicates that simultaneously targeting Etk and Src could be a promising approach to overcome drug resistance in prostate cancer.

• Authors: Wenchang Guo, Ruiwu Liu, Gaurav Bhardwaj, Ai-Hong Ma, Chun Changou, Joy C Yang, Yuanpei Li, Caihong Feng, Yan Luo, Anisha Mazloom, Eduardo Sanchez, Yan Wang, Wenzhe Huang, Randen Patterson, Christopher P Evans, Kit S Lam, Hsing-Jien Kung
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e70910 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23967135 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 2-(dibenzo(b,d)furan-2-yl)-7-phenyl-1-(3-(piperidin-1-yl)propyl)-1H-imidazo(4,5-g)quinoxalin-6(5H)-one
• Benzofurans
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Quinoxalines
• STAT3 Transcription Factor
• Adenosine Triphosphate
• BMX protein, human
• Protein-Tyrosine Kinases
• src-Family Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis (drug effects)
• Benzofurans (pharmacology)
• Binding Sites
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation (drug effects)
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Male
• Mice
• Models, Molecular
• Phosphorylation (drug effects)
• Prostatic Neoplasms (metabolism, pathology)
• Protein Binding
• Protein Conformation
• Protein-Tyrosine Kinases (antagonists & inhibitors, chemistry)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors)
• Quinoxalines (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• src-Family Kinases (antagonists & inhibitors, chemistry)