Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment

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 IC of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50-200 μmol/L) induced cell cycle arrest at G/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·d, 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·d, 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.

Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

“… [ 44 ] PC-3 DAS3 Gastric 20.5 Bcl-2 Inhibited viability of BCG-823 in vitro and modulated Bcl-2. [ 45 ] BGC-823 DAS3 Breast 1.78 MMP2/9 Suppressed metastasis [ 46 ] MDA-MB-231 HS 578t DAS3 Colon 8.91 Focal adhesion kinase (FAK Inhibition of angiogenesis [ 47 ] HT29 DAS3 A375 17.8 Mitochondrial caspase pathway Increase in ROS [ 48 ] Skin DAS3 Lymphoma 3.56 NF-κB Apoptosis in primary effusion lymphoma [PEL] [ 49 ] BC2, BC3, BCBL1, HBL6 DAS3 Prostate 3.56 Androgen receptor (AR) Decrease in AR levels [ 50 ] LNCaP, C4-2, TRAMP-C1 DAS3 Glioblastoma 17.8 Bcl-2 Inhibition and proliferation [ 51 ] U87MG Neuroblastoma SH-SY5Y …”

Phytochemicals for the Prevention and Treatment of Gastric Cancer: Effects and Mechanisms

“…Furthermore, combined treatment of diallyl trisulfide and docetaxel showed a synergistic effect against gastric cancer through inducing G 2 /M cell cycle arrest and apoptosis with increased level of metallothionein 2A (MT2A) and inhibition of NF-κB signaling in BGC823 cells [110]. In another study, diallyl trisulfide enhanced the potency of cisplatin against gastric cancer through the activation of p38 and JNK MAPK signaling pathway, and downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Akt pathway in vitro and in vivo [111]. Additionally, 6-gingerol increased the cisplatin sensitivity of HGC-27 cells via the suppression of cell proliferation, migration, and invasion by inactivating PI3K/Akt signaling pathway [112].…”

Garlic and its Active Compounds: A Novel Strategy to Fight Diseases Through Modulating Biological Activities

“…Besides, increased E-cadherin and decreased MMP-9 expression levels were observed in diallyl trisulfide -treated tumor tissues. 134 Strategies to overcome the low bioavailability of garlic and its compound…”