Andrographolide sensitizes cisplatin-induced apoptosis via suppression of autophagosome-lysosome fusion in human cancer cells.
Suppression of autophagy has been increasingly recognized as a novel cancer therapeutic approach. Andrographolide (Andro), a diterpenoid lactone isolated from an herbal plant Andrographis paniculata, is known to possess anti-inflammatory and anticancer activity. In this study, we sought to examine the effect of Andro on autophagy, and to evaluate whether such effect is relevant to the sensitization effect of Andro on apoptosis induced by DNA damage agents in cancer cells. First, we found that Andro is able to significantly enhance autophagic markers in various cancer cell lines, including GFP-LC3 puncta and LC3-II level. Interestingly, Andro treatment also led to marked increase of p62 protein level and addition of chloroquine (CQ) failed to further enhance either LC3-II or p62 level, indicating that Andro is likely to suppress autophagic flux at the maturation and degradation stage. Next, we provided evidence that Andro inhibits autophagosome maturation not by affecting the lysosomal function, but by impairing autophagosome-lysosome fusion. Lastly, we demonstrated that treatment with cisplatin, a DNA damage agent, induces autophagy in cancer cells. Importantly, Andro is capable of sensitizing cisplatin-induced cell killing determined with both short-term apoptosis assays and long-term clonogenic test, via suppression of autophagy, a process independent of p53. In summary, these observations collectively suggest that Andro could be a promising anti-cancer agent in combination therapy via its potent inhibitory effect on autophagy by disrupting autophagosome-lysosome fusion.
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Jing
J
Zhou
Shuai-Er
SE
Hu
Shi-Hao
SH
Tan
Ruoxi
R
Cao
Yiyang
Y
Chen
Dajing
D
Xia
Xinqiang
X
Zhu
Xing-Fen
XF
Yang
Choon-Nam
CN
Ong
Han-Ming
HM
Shen
D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008561:Membrane Fusion / Q000187:drug effects*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015415:Biomarkers; D004224:Diterpenes; D016159:Tumor Suppressor Protein p53; C030419:andrographolide; D002945:Cisplatin