Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers cancer cell death via its association with death receptors on the cell membrane, but exerts negligible side effects on normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients exhibited resistance to TRAIL treatment in clinical trials, and the mechanism varies. In this study, we described for the first time that toosendanin (TSN), a triterpenoid derivative used in Chinese medicine for pain management, could significantly sensitize human primary NSCLC cells or NSCLC cell lines to TRAIL-mediated apoptosis both in vitro and in vivo, while showing low toxicity against human primary cells or tissues. The underlying apoptotic mechanisms involved upregulation of death receptor 5 (DR5) and CCAAT/enhancer binding protein homologous protein, which is related to the endoplasmic reticulum stress response, and is further associated with reactive oxygen species generation and Ca2+ accumulation. Surprisingly, TSN also induced autophagy in NSCLC cells, which recruited membrane DR5, and subsequently antagonized the apoptosis-sensitizing effect of TSN. Taken together, TSN can be used to sensitize tumors and the combination of TRAIL and TSN may represent a useful strategy for NSCLC therapy; moreover, autophagy serves as an important drug resistance mechanism for TSN.

• Authors: Xin Li, Ming You, Yong-Jian Liu, Lin Ma, Pei-Pei Jin, Ri Zhou, Zhao-Xin Zhang, Baojin Hua, Xiao-Jun Ji, Xiao-Ying Cheng, Fangzhou Yin, Yan Chen, Wu Yin
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 42748 (02 17 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28209994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CCAAT-Enhancer-Binding Proteins
• Drugs, Chinese Herbal
• Reactive Oxygen Species
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• toosendanin
• Calcium

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Calcium (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drugs, Chinese Herbal (administration & dosage, pharmacology, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy)
• Mice
• Reactive Oxygen Species (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology, therapeutic use)