Combination of the natural compound Periplocin and TRAIL induce esophageal squamous cell carcinoma apoptosis in vitro and in vivo: Implication in anticancer therapy

Abstract

BackgroundEsophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~ 30% patients can survive this disease for more than 5 years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity.MethodsWe used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo.ResultsIn our studies, we found that CPP alone or in combination with TRAIL could inhibit the proliferation of ESCC cells and induce apoptosis, and we certificated that combination of two agents exert synergized functions. For the first time, we identified FoxP3 as a key transcriptional repressor for both DR4 and DR5. By down-regulating FoxP3, CPP increases the expression of DR4/DR5 and renders ESCC cells much more sensitive to TRAIL. We also showed that CPP reduced the expression of Survivin by inhibiting the activity of Wnt/β-catenin pathway. All these contributed to synergistic activity of CPP and TRAIL on ESCC cells in vitro and in vivo.ConclusionOur data suggest that CPP and TRAIL could be further explored as potential therapeutic approach for esophageal cancer.

Oleic Acid and Insulin as Key Characteristics of T2D Promote Colorectal Cancer Deterioration in Xenograft Mice Revealed by Functional Metabolomics

“…Herein, we assumed that insulin and OA might have a synergistic effect in promoting the proliferation of HCT116. To prove this, we referred to Jin's formula (21) to calculate the combination index of insulin (50 nM) and OA (50, 100, 200, 500, and 1,000 mM). A synergistic effect is usually acknowledged when the combination index exceeds 1.15.…”

Demethylzelasteral inhibits proliferation and EMT via repressing Wnt/β-catenin signaling in esophageal squamous cell carcinoma

“…β-catenin acts as a key indicator for cell fatalization and EMT in metastatic cancers. Moreover, it was related to drug resistance and recurrence in patients suffering from esophageal cancer [38][39][40]. T-96 inhibits the expression of Wnt/ β-catenin signaling downstream target genes, thus inhibiting Wnt/β-catenin signaling activities.…”

Inhibitory Effects of Periplocin on Lymphoma Cells: A Network Pharmacology Approach and Experimental Validation

“… 10 Furthermore, the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and periplocin had a greater inhibitory effect on both gastric cancer and esophageal squamous cell carcinoma cell viability than periplocin or TRAIL alone, both in vitro and in vivo. 15 , 16 Periplocin also inhibits the growth of colon cancer cells and downregulates the expression of c-myc, both in vitro and in vivo, via beta-catenin/TCF signaling. 14…”