Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment.
Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25-400 μmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50-200 μmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20-40 mg·kg-1·d-1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg·kg-1·d-1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.
School of Pharmaceutical Sciences, Shandong University, Ji-nan 250012, China.
Xiao-Yan
XY
Jiang
School of Pharmaceutical Sciences, Shandong University, Ji-nan 250012, China.
Xiao-Song
XS
Zhu
School of Pharmaceutical Sciences, Shandong University, Ji-nan 250012, China.
Hong-Ya
HY
Xu
School of Pharmaceutical Sciences, Shandong University, Ji-nan 250012, China.|Shandong Provincial Key Laboratory of Mucosal and Transdermal Drug Delivery Technologies, Shandong Academy of Pharmaceutical Sciences, Ji-nan 250101, China.|Jiangsu Shengshi Kangde Biotech Corporation, Lianyungang 222006, China.
Zhong-Xi
ZX
Zhao
School of Pharmaceutical Sciences, Shandong University, Ji-nan 250012, China.
Si-Ying
SY
Li
Jiangsu Shengshi Kangde Biotech Corporation, Lianyungang 222006, China.
Shan-Zhong
SZ
Li
Jiangsu Shengshi Kangde Biotech Corporation, Lianyungang 222006, China.
Jian-Hua
JH
Cai
Jiangsu Shengshi Kangde Biotech Corporation, Lianyungang 222006, China.
Ji-Min
JM
Cao
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013440:Sulfides; C042577:diallyl trisulfide; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin