A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis.
A new series of 20 brominated chalcone derivatives were designed, synthesized, and investigated for their effects against the growth of four cancer cell lines (EC109, SKNSH, HepG2, MGC803). Among them, compound 19 which given chemical name of H72, was the most potent one on gastric cancer cell lines (i.e. MGC803, HGC27, SGC7901) with IC50s ranged from 3.57 to 5.61μM. H72 exhibited less cytotoxicity to non-malignant gastric epithelial cells GES-1. H72 treatment of MGC803 and HGC27 induced generation of reactive oxygen species (ROS) leading to activation of caspase 9/3 cascade and mitochondria mediated apoptosis. H72 also up-regulated the expression of DR5, DR4 and BimEL, and down-regulated the expression of Bid, Bcl-xL, and XIAP. N-acetyl cysteine (NAC), a ROS scavenger completely blocked these effects of H72 in MGC803 cells. Intraperitoneal administration of H72 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that H72 is a lead brominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Saiyang
S
Zhang
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Tingyu
T
Li
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Yanbing
Y
Zhang
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Hongde
H
Xu
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Yongchun
Y
Li
Department of Urology, University of California, Irvine, Orange, USA; Department of Pharmacology, University of California, Irvine, Orange, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Orange, USA.
Xiaolin
X
Zi
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China.
Haiyang
H
Yu
Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Erqi District, Zhengzhou, Henan 450001, China.
Jinfeng
J
Li
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: cyjin@zzu.edu.cn.
Cheng-Yun
CY
Jin
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: liuhm@zzu.edu.cn.
Hong-Min
HM
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001966:Bromine / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects*
D047188:Chalcones; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D001966:Bromine
Apoptosis; Brominated chalcone; Gastric cancer cells; ROS