PMID- 30870718
OWN - NLM
STAT- MEDLINE
DCOM- 20190806
LR  - 20190806
IS  - 1950-6007 (Electronic)
IS  - 0753-3322 (Linking)
VI  - 113
DP  - 2019 May
TI  - beta-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in 
      non-small cell lung cancer.
PG  - 108769
LID - S0753-3322(19)30525-6 [pii]
LID - 10.1016/j.biopha.2019.108769 [doi]
AB  - AIMS: In this study, we examined whether beta-apopicropodophyllin (APP) could act as 
      a radiosensitizer in non-small cell lung cancer (NSCLC) cells. MAIN METHODS: The 
      in vitro radiosensitizing activity of APP was demonstrated with clonogenic assay, 
      immunoblotting, Annexin V-Propidium iodide (PI) assay, BrdU incorporation, 
      detection of mitochondrial ROS/intracellular of H(2)O(2), mitochondrial membrane 
      potential detection, and performing of isolation of mitochondrial and cytosolic 
      fractions. The in vivo radiosensitizing activity of APP was determined in 
      xenografted mice with co-treatment of APP and IR based on measurement of tumor 
      volumes and apoptotic cell death. KEY FINDINGS: The results of a clonogenic assay 
      indicated that a combination of APP and gamma-ionizing radiation (IR) inhibits cell 
      growth and increases cell death in NSCLC cells. Several signal transduction 
      pathways were examined for their potential involvement in the apparent 
      radiosensitization effect of APP, as assessed by immunoblotting analyses and 
      mitochondrial potential determination in vitro. Treatment of NCI-H460 cells with 
      15 nM APP and NCI-H1299 cells with 10 nM APP yielded dose-enhancement ratios of 
      1.44 and 1.24, respectively. Enhanced ER stress, disrupted mitochondrial membrane 
      potential, and increased reactive oxygen species (ROS) were observed in cells 
      co-treated with APP and IR, and this was followed by the cytosolic release of 
      cytochrome c and consequent activation of caspase-3 and -9. Notably, inhibition 
      of JNK, which prevents caspase activation, blocked the APP/IR-induced activations 
      of ER stress and apoptotic cell death. In NCI-H460 or NCI-H1299 cell-xenografted 
      mice, APP/IR treatment delayed the time it took tumors to reach a threshold size 
      by 22.38 and 16.83 days, respectively, compared with controls, to yield 
      enhancement factors of 1.53 and 1.38, respectively. SIGNIFICANCE: APP has a 
      radiosensitizing function derived from its ability to induce apoptotic cell death 
      via activation of ER stress, disruption of mitochondrial membrane potential, and 
      induction of the caspase pathway.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Masson SAS.. All rights 
      reserved.
FAU - Kim, Ju Yeon
AU  - Kim JY
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Cho, Jeong Hyun
AU  - Cho JH
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Kim, Eun Mi
AU  - Kim EM
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Shin, Hyun-Jin
AU  - Shin HJ
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Hwang, Sang-Gu
AU  - Hwang SG
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Song, Jie-Young
AU  - Song JY
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Um, Hong-Duck
AU  - Um HD
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea.
FAU - Park, Jong Kuk
AU  - Park JK
AD  - Division of Applied Radiation Bioscience, Korea Institute of Radiological and 
      Medical Sciences, Seoul, Republic of Korea. Electronic address: 
      jkpark@kirams.re.kri.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20190311
PL  - France
TA  - Biomed Pharmacother
JT  - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
JID - 8213295
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (beta-apopicropodophyllin)
RN  - 9000-55-9 (Podophyllin)
RN  - BBX060AN9V (Hydrogen Peroxide)
MH  - Animals
MH  - Apoptosis/drug effects/radiation effects
MH  - Carcinoma, Non-Small-Cell Lung/pathology/*radiotherapy
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum Stress/drug effects/radiation effects
MH  - Humans
MH  - Hydrogen Peroxide/metabolism
MH  - Lung Neoplasms/pathology/*radiotherapy
MH  - Membrane Potential, Mitochondrial
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Mitochondria/metabolism
MH  - Podophyllin/administration & dosage/*pharmacology
MH  - Radiation-Sensitizing Agents/administration & dosage/*pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Apoptosis
OT  - ER stress
OT  - Non-small cell lung cancer
OT  - ROS
OT  - Radiosensitizer
OT  - beta-Apopicropodophylli
EDAT- 2019/03/15 06:00
MHDA- 2019/08/07 06:00
CRDT- 2019/03/15 06:00
PHST- 2019/02/01 00:00 [received]
PHST- 2019/03/07 00:00 [revised]
PHST- 2019/03/07 00:00 [accepted]
PHST- 2019/03/15 06:00 [pubmed]
PHST- 2019/08/07 06:00 [medline]
PHST- 2019/03/15 06:00 [entrez]
AID - S0753-3322(19)30525-6 [pii]
AID - 10.1016/j.biopha.2019.108769 [doi]
PST - ppublish
SO  - Biomed Pharmacother. 2019 May;113:108769. doi: 10.1016/j.biopha.2019.108769. Epub 
      2019 Mar 11.