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Pharmacol Rep. 2017 Oct;69(5):878-884. doi: 10.1016/j.pharep.2017.04.007. Epub 2017 Apr 13.

Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells.

Author information

1
Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
2
Department of Orthopedic Surgery, Hana Hospital, Changwon, Republic of Korea.
3
Department of Herbal Formula, Medical Research Center (MRC-GHF), College of Oriental Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.
4
Department of Orthopedic Surgery, Pusan National University School of Medicine, Busan, Republic of Korea.
5
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Republic of Korea. Electronic address: jij@ajou.ac.kr.
6
Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, Republic of Korea; Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, Republic of Korea. Electronic address: ahnsc@pusan.ac.kr.

Abstract

BACKGROUND:

A natural compound deoxypodophyllotoxin (DPT) possesses potent anti-proliferative and anti-tumor properties on several cancer types. It triggers cell cycle arrest followed by apoptosis through various cellular processes. However, it is limited to the action mechanism of DPT-mediated cell death modes via apoptosis and autophagy.

METHODS:

Cell viability assay, morphological changes, annexin-V/propidium iodide (PI) assay, reactive oxygen species (ROS), acridine orange staining, and Western blot analyses were evaluated.

RESULTS:

We demonstrated that DPT induced both apoptosis and autophagy via production of mitochondrial reactive oxygen species (ROS). DPT suppressed the PI3K/AKT/mTOR signaling cascades to lead autophagy process, resulting from conversion of light chain 3-I (LC3-I) into LC3-II and acidic vesicular organelles (AVOs) formation. Even if DPT-induced ROS were occurred in both apoptosis and autophagy, inhibition of ROS generation enhanced cell viability. Otherwise, 3-methyladeine (3-MA) impeding on autophagy accelerated an apoptotic response caused by DPT. Therefore, these findings suggest that DPT triggers cytoprotective autophagy against cytotoxic apoptosis.

CONCLUSION:

Autophagy is required for cell survival by inhibition of apoptosis through down-regulation of PI3K/AKT/mTOR pathway against DPT-induced apoptosis in U2OS cells.

KEYWORDS:

Apoptosis; DPT; Deoxypodophyllotoxin; ROS; Reactive oxygen species

PMID:
28623712
DOI:
10.1016/j.pharep.2017.04.007
[Indexed for MEDLINE]

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