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Phytomedicine. 2019 Jan;52:147-156. doi: 10.1016/j.phymed.2018.09.221. Epub 2018 Sep 26.

Antimalarial Dihydroartemisinin triggers autophagy within HeLa cells of human cervical cancer through Bcl-2 phosphorylation at Ser70.

Author information

1
Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Clinical Laboratory, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China.
2
Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China; Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang 050081, China. Electronic address: sxlsunshine@sina.com.
3
Hebei Provincial Engineering Laboratory of Plant Bioreactor Preparation Technology, Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China.
4
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China.
5
Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang 050081, China.

Abstract

BACKGROUND:

As an effective antimalarial medicine, Dihydroartemisinin (DHA) has therapeutic potential on human cervical cancer. However, its working mechanism has not been elucidated.

PURPOSE:

This study aimed to investigate the reversal effect of DHA on human cervical cancer HeLa cells, and explored its mechanism of action in vitro and in vivo.

STUDY DESIGN/METHODS:

The effect and mechanism of DHA on HeLa cells was examined by using CCK-8 assay, flow cytometry, transmission electron microscopy, immunofluorescence, and Western blot analysis in human hepatocellular carcinoma cells.

RESULTS:

In this study, it was confirmed that DHA had statistically equivalent anti-tumor efficiency in HeLa cells with a clinical chemotherapeutic agent of cisplatin. Meanwhile, DHA triggered autophagy, where LC3B-II expression was dose-dependently increased. Further, it was revealed that DHA promotes reactive oxygen species (ROS) generation, with DNA double-strand breaks (DSB) damage, as up-regulation of γH2AX protein and foci formation. Interestingly, we firstly demonstrated that DHA induced autophagy through promotion of the phosphorylation of Bcl-2 (Ser70), independent of the phosphorylated JNK1/2 (Thr183/Tyr185). Moreover, DHA-treated HeLa cells displayed an increase in the pro-autophagic protein Beclin-1 with downregulated the phospho-mTOR (Ser2448). Furthermore, upregulated pro-apoptotic protein Bak-1, but not Bax, suggesting Bak-1 is included in DHA-induced autophagy.

CONCLUSION:

Therefore, DHA upregulates the phosphorylation of Bcl-2 (Ser70) and mTOR (Ser2448) and induces autophagic cell death in Hela cells. This study provided a mechanism to support DHA, an autophagy inducer, as a potential therapeutic agent for human cervical cancer.

KEYWORDS:

Autophagy; Bcl-2; DNA double-strand break; Dihydroartemisinin; ROS

PMID:
30599894
DOI:
10.1016/j.phymed.2018.09.221
[Indexed for MEDLINE]

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