1. Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment
- Author
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Shanzhong Li, Xiaosong Zhu, Hongya Xu, Jimin Cao, Zhongxi Zhao, Siying Li, Xiaoyan Jiang, and Jianhua Cai
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cell Survival ,NF-E2-Related Factor 2 ,p38 mitogen-activated protein kinases ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Sulfides ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Stomach Neoplasms ,In vivo ,Tumor Cells, Cultured ,Animals ,Humans ,Medicine ,Pharmacology (medical) ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Cisplatin ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,business.industry ,JNK Mitogen-Activated Protein Kinases ,Neoplasms, Experimental ,General Medicine ,Allyl Compounds ,Oncogene Protein v-akt ,030104 developmental biology ,Diallyl trisulfide ,chemistry ,030220 oncology & carcinogenesis ,Female ,Original Article ,Drug Screening Assays, Antitumor ,business ,medicine.drug - Abstract
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 IC50 of 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.
- Published
- 2017