Abstract
Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment.
Highlights
Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancerrelated death in the world[1]
After 25-minute www.impactjournals.com/oncotarget incubation in the phosphate buffer, curcumin lost more than 45% of its original intensity, while WZ35 showed no degradation under the same condition (Figure 1B)
WZ35 is the one of mono-carbonyl analog of curcumin designed by our group and shows higher chemical stability than curcmin in both PH7.4 phosphate buffer and cell culture medium (Figure 1B and 1C)
Summary
Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancerrelated death in the world[1]. This aggressive disease continues to be a major public health issue worldwide. Surgery is the mainly curative treatment for localized gastric cancer. The high risk of relapse after surgery has led to a search for strategies to prevent relapse and to improve survival for gastric cancer patients. Chemotherapy in advanced gastric cancer is an important issue because the majority of patients with gastric cancer develop metastases during the course of their disease[3, 4]. Severe side effects and complications such as hematological and gastrointestinal toxicities of current anticancer drugs become major problems in the clinical setting, which highlights the urgent need for novel effective and less toxic therapeutic approaches[5, 6]
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