Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells

• Published in: Cell death & disease Vol. 11; no. 8; p. 611
• Main Authors: Wang, Kun, Liu, Xiaodong, Liu, Quanmeng, Ho, Idy ht, Wei, Xianli, Yin, Ting, Zhan, Yujuan, Zhang, Wenjing, Zhang, Wenbo, Chen, Bonan, Gu, Jiangyong, Tan, Yuhui, Zhang, Lin, Chan, Matthew Tv, Wu, William Kk, Du, Biaoyan, Xiao, Jianyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-08-2020; Springer Nature B.V
• Subjects: 13/1; 13/2; 13/31; 13/89; 14/19; 14/28; 42/109; 42/44; 631/154/436; 631/67/1612; 96/34; Acidification; Acidity; Acridine orange; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Cathepsin B; Cathepsin D; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - pathology; Lung Neoplasms - ultrastructure; Lysosomes; Lysosomes - drug effects; Lysosomes - metabolism; Mice, Inbred BALB C; Mice, Nude; Models, Biological; N-Acetyl-L-cysteine; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Paclitaxel; Paclitaxel - pharmacology; Phagocytosis; Phagosomes; Reactive oxygen species; Reactive Oxygen Species - metabolism; Synergism; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02880-5

Autophagy inhibition has been demonstrated to increase the efficacy of conventional chemotherapy. In this study, we identified hederagenin, a triterpenoid derived from
Hedera helix
, as a potent inhibitor of autophagy and then hypothesized that hederagenin might synergize with chemotherapeutic drugs (e.g., cisplatin and paclitaxel) to kill lung cancer cells. Firstly, we observed that hederagenin induced the increased autophagosomes in lung cancer cells concomitantly with the upregulation of LC3-II and p62, which indicated the impairment of autophagic flux. The colocalization assay indicated hederagenin could not block the fusion of lysosomes and autophagosomes, whereas the lysosomal acidification might be inhibited by hederagenin as revealed by the reduced staining of acidity-sensitive reagents (i.e., Lysotracker and acridine orange). The aberrant acidic environment then impaired the function of lysosome, which was evidenced by the decrease of mature cathepsin B and cathepsin D. Lastly, hederagenin, in agree with our hypothesis, promoted pro-apoptotic effect of cisplatin and paclitaxel with the accumulation of reactive oxygen species (ROS); while the synergistic effect could be abolished by the ROS scavenger, N-acetyl-L-cysteine. These data summarily demonstrated hederagenin-induced accumulation of ROS by blocking autophagic flux potentiated the cytotoxicity of cisplatin and paclitaxel in lung cancer cells.