CecropinXJ inhibits the proliferation of human gastric cancer BGC823 cells and induces cell death in vitro and in vivo

Abstract

Abstract. We have shown that an antimicrobial peptide (AMP) cecropinXJ isolated from the larvae of Bombyx mori selectively inhibits the proliferation of cancer cells. However, the mechanism remains to be determined. In the present study, we examined the antitumor activity of cecropinXJ against human gastric cancer BGC823 cells and explored the mechanism. The results showed that cecropinXJ inhibited the growth of gastric cancer BGC823 cells in vitro and in vivo. MTT and colony formation assays indicated that cecropinXJ suppressed cell proliferation and reduced colony formation of BGC823 cells in a dose-and time-dependent manner, but without inhibitory effect on normal gastric epithelia GES-1 cells. S-phase arrest in BGC823 cells was observed after treatment with cecropinXJ. Annexin V/PI staining suggested that cecropinXJ induced both early and late phases of apoptosis through activation of mitochondrial-mediated caspase pathway, upregulation of Bax expression and downregulation of Bcl-2 expression. Additionally, cecropinXJ treatment increased reactive oxygen species (ROS) production, disrupted the mitochondrial membrane potential (Δψ m ) and led to release of cytochrome c. Importantly, in vivo study showed that cecropinXJ significantly prevented the growth of xenograft tumor in the BGC823-bearing mice, possibly mediated by the induction of apoptosis and inhibition of angiogenesis. These results suggest that cecropinXJ may be a promising therapeutic candidate for the treatment of gastric cancer. IntroductionGastric cancer is one of the most common malignant tumors, >70% of new cases and deaths occur in developing countries each year (1). In China, the incidence and mortality rate of gastric cancer are increasing. Although there are distinct discrepancies in diagnosis, prognosis, and treatment efficacy for gastric cancer patients, the 5-year survival rate of gastric cancer is generally <20% (2). At present, the management of gastric cancer includes surgery, radiotherapy, conventional chemotherapy, molecular targeted therapy and biological therapy, but these methods have not reached expected clinical efficacy, which mainly focus on mass cell killing without high specificity and often causes severe side-effects and toxicities. Moreover, recurrences and metastasis frequently occur in the majority of patients (2). Hence, it is urgent to explore safe and effective therapeutic agents for gastric cancer to improve the survival rate and quality of life.Antimicrobial peptides (AMPs) are evolutionarilyconserved components of the innate immune system (3), which exert their activities against a broad range of microbial pathogens. Compared to conventional treatments, AMPs have many advantages, such as specific cytotoxicity for cancer cells, ability to bypass the multidrug-resistance mechanism, and additive effects in combination therapy (4), suggesting that AMPs has potential as a novel antitumor agent for the treatment of cancer.AMPs can directly kill cancer cells by a cell membranelytic effect (5), or trigger apoptosis in can...

Therapeutic effects of antimicrobial peptide on malignant ascites in a mouse model

“…CecropinXJ may effectively inhibit the proliferation of human gastric cancer BGC823 cells ( 12 ). Studies investigating the effect of cecropinXJ on the growth of malignant ascites tumors are scarce.…”

“…CecropinXJ demonstrates a broad activity against bacteria and fungi ( 10 , 11 ). Previous studies have revealed that cecropinXJ may inhibit the proliferation of human BGC823 gastric cancer cells in vitro ( 12 ), whereas, it demonstrates no hemolytic effects against human erythrocytes and no toxicity to healthy mammalian cells ( 13 , 14 ). However, to the best of the author's knowledge, no relevant studies have been performed to date that explore the effects of cecropinXJ on the growth of tumor-associated ascites in human gastric cancer.…”

Combination of cecropinXJ and LY294002 induces synergistic cytotoxicity, and apoptosis in human gastric cancer cells via inhibition of the PI3K/Akt signaling pathway

“…Over-activated Akt achieves its anti-apoptotic effects by phosphorylating various substrates such as Bad (39) and caspase-9 (40). Previous studies have revealed that cecropinXJ may inhibit Bad phosphorylation (16,17). p-Bad may combine with Bcl-2 or Bcl-XL on the mitochondrial membrane to prevent the release of cytochrome c from the mitochondria and the activation of caspase-9 (41).…”

“…CecropinXJ elicits a broad spectrum of effects against bacteria and fungi (14,15). Our previous studies indicated that cecropinXJ exhibits anti-tumor and anti-proliferation activities, and an apoptosis-promoting effect on human gastric cancer AGS (16), and BGC823 cells (17). In addition, apoptosis is mediated by the Combination of cecropinXJ and LY294002 induces synergistic cytotoxicity, and apoptosis in human gastric cancer cells via inhibition of the PI3K/Akt signaling pathway mitochondrial apoptotic pathway.…”

Antitumor Effects of Nordihydroguaiaretic Acid (NDGA) in Bladder T24 Cancer Cells are Related to Increase in ROS Production and Mitochondrial Leak Respiration

“…ROS production increase and mitochondrial membrane potential (m) disruption induced by several natural compounds have been associated to the growth inhibition of different cancer models [12][13][14]. Then, T24 cells were treated with 20 µM NDGA for 2 to 72 h and m ( Figure 2A) and ROS production ( Figure 2B) were evaluated.…”