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Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment
- Source :
- Acta Pharmacologica Sinica. 38:1048-1058
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
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.
- 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
Subjects
Details
- ISSN :
- 17457254 and 16714083
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....ba65b5767a7aeb8a9c1db88070e38046