DADS suppresses human esophageal xenograft tumors through RAF/MEK/ERK and mitochondria-dependent pathways.

Xiaoran Yin,Dong Liu,Xiaoning Li,Xinlian Liu,Xijing Wang,Kun Zhuang,Cheng Feng,Fuchun Jing,Chenlei Cai,Xinghuan Xue,Hongbing Ma,Jun Zhang,Rongrui Liang,Jun Wang

doi:10.3390/ijms150712422

Xiaoran Yin, Dong Liu + Show 12 more

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https://doi.org/10.3390/ijms150712422

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Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro–apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma.

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Esophageal carcinoma is among the most common tumors in the world, ranking eighth in occurrence and sixth in mortality [1]
The expression level of MEK1 decreased in 40 mg/kg Diallyl disulfide (DADS) group (p < 0.01, Figure 7c). These results suggested that DADS had a profound effect on the apoptosis in ECA109 xenograft tumor, which might be correlated with the RAF/MEK/ERK pathway
Our results showed that the apoptosis of DADS was caspase-dependent, since caspase-3 was active during this procedure (Figures 5a,c and 6a,c,e) and that the pre–treatment with caspase-3 inhibitor (Ac-DEVD-CHO) could dramatically block the apoptosis induced by DADS (Figure 3b,d)

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Introduction

Esophageal carcinoma is among the most common tumors in the world, ranking eighth in occurrence and sixth in mortality [1]. 70% of global esophageal carcinoma cases occur in China and the five–year survival rate is only 10% [2]. Esophageal carcinoma patients in the primary stage can be cured by surgical resection. A majority of patients in the advanced stage eventually succumb to this disease [3]. Radiotherapy and chemotherapy are regarded as important parts of the systemic therapy for metastatic esophageal carcinoma, the success of such treatments have been weakened by their severe systemic toxicities and local irritating effects. In order to enhance efficacy and reduce toxicity, researchers have urgently tried to develop novel regimens with fewer side effects against esophageal carcinoma [4]

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