A novel small-molecule YLT205 induces apoptosis in human colorectal cells via mitochondrial apoptosis pathway in vitro and inhibits tumor growth in vivo.
BACKGROUND
Colorectal cancer continues to be one of the most common causes of cancer death, and the poor survival rates and liver metastases at the time of diagnosis urgently need more effective strategy for colorectal cancer treatment.


METHODS
The activities of N-(5-bromopyridin-2-yl)-2-((6-(2-chloroacetamido)benzo[d]thiazol-2-yl)thio)acetamide (YLT205), which is a novel small molecule compound synthesized by us, were investigated using MTT assay, flow cytometry, western blotting and mice tumor xenograft models.


RESULTS
YLT205 induced apoptosis of human colorectal cell lines in a dose-dependent manner. The occurrence of apoptosis was associated with activation of caspases-9 and -3, down-regulation of Bcl-2 and up-regulation of Bax in HCT116 cells. Moreover, YLT205 disrupted mitochondrial membranes and induced the release of cytochrome c into cytosol. Impaired phosphorylation of p44/42 mitogen-activated protein kinase was also observed while the expression of phosphorylated protein kinase B (Akt) was not affected. Furthermore, in HCT116 and SW620 tumor-bearing nude mice models, YLT205 dose-dependently inhibited tumor growth without obvious adverse effects. Immunohistochemistry analyses revealed YLT205 also induced apoptosis and inhibited tumor cell proliferation in vivo.


CONCLUSIONS
These studies suggested that YLT205 might be a potential drug candidate for human colorectal cancer therapy.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Yongxia
Y
Zhu
Yong
Y
Xia
Tinghong
T
Ye
Xuanhong
X
Shi
Xuejiao
X
Song
Li
L
Liu
Jun
J
Zeng
Ningyu
N
Wang
Yong
Y
Luo
Yuanping
Y
Han
Luoting
L
Yu
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D005419:Flavonoids / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000081:Acetamides; D000590:Amino Acid Chloromethyl Ketones; D052160:Benzothiazoles; D005419:Flavonoids; C000594303:N-(5-bromopyridin-2-yl)-2-((6-(2-chloroacetamido)benzo(d)thiazol-2-yl)thio)acetamide; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D045304:Cytochromes c; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one