A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumor activity in solid malignancies

Song Xuejiao; Xia Yong; Wang Ningyu; Zhang Lidan; Shi Xuanhong; Xu Youzhi; Ye Tinghong; Shi Yaojie; Zhu Yongxia; Yu Luoting

doi:10.1371/journal.pone.0063900

A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumor activity in solid malignancies

PLoS One. 2013 May 30;8(5):e63900. doi: 10.1371/journal.pone.0063900. Print 2013.

Authors

Song Xuejiao¹, Xia Yong, Wang Ningyu, Zhang Lidan, Shi Xuanhong, Xu Youzhi, Ye Tinghong, Shi Yaojie, Zhu Yongxia, Yu Luoting

Affiliation

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

Abstract

Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67-positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / chemistry*
Aminopyridines / pharmacology*
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Benzothiazoles / chemistry*
Benzothiazoles / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cytochromes c / metabolism
Down-Regulation / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Membrane Potential, Mitochondrial / drug effects
Mice
Mitochondria / drug effects*
Mitochondria / metabolism
Mitogen-Activated Protein Kinases / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein / metabolism

Substances

2-chloro-N-(2-(2-(5-methylpyridin-2-ylamino)-2-oxoethylthio)benzo(d)thiazol-6-yl) acetamide
Aminopyridines
Antineoplastic Agents
Benzothiazoles
Proto-Oncogene Proteins c-bcl-2
bcl-2-Associated X Protein
Cytochromes c
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinases
benzothiazole

Grants and funding

This work was supported by Shijiazhuang Pharmaceutical Group Co., Ltd. (project name SKLB163; contract number 11H0684). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.