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Biomed Pharmacother. 2019 May;113:108769. doi: 10.1016/j.biopha.2019.108769. Epub 2019 Mar 11.

β-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in non-small cell lung cancer.

Author information

1
Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
2
Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. Electronic address: jkpark@kirams.re.kri.

Abstract

AIMS:

In this study, we examined whether β-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 H2O2, 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 γ-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.

KEYWORDS:

Apoptosis; ER stress; Non-small cell lung cancer; ROS; Radiosensitizer; β-Apopicropodophylli

PMID:
30870718
DOI:
10.1016/j.biopha.2019.108769
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