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Podophyllotoxin acetate enhances γ-ionizing radiation-induced apoptotic cell death by stimulating the ROS/p38/caspase
Jae Yeon Choi1, Hyun-Ji Cho2, Sang-Gu Hwang2
1Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; Department of Food and Microbial Technology, College of Natural Sciences, Seoul Women's University, Seoul, Korea.
Abstract:
To develop a new radiosensitizer against non-small cell lung cancer cells, we screened a natural product library for growth-inhibitory compounds. PA was found to be cytotoxic toward NCI-H460 cells, and its IC₅₀ value was determined. The radiosensitizer effects of PA were tested at its IC₅₀ value in clonogenic and cell-counting assays. The intracellular mechanism underlying this effect was determined by immunoblotting and by measuring propidium iodide uptake and ROS generation. The radiosensitizer activity of PA in vivo was tested in nude mice by treating with PA and IR, and measuring tumor volume and assessing apoptosis. PA, tested at its experimentally determined IC₅₀ value (12 nM), enhanced IR-induced death of NCI-H460 cells by increasing apoptosis, yielding a mean calculated dose-enhancement ratio of 1.67. Combination with PA and IR also increased the production of ROS, which subsequently induced phosphorylation of p38, suppressed phosphorylation of ERK, and activated caspase-3, -8, and -9. Notably, inhibition of ROS production prevented p38 phosphorylation, and inhibition of ROS production or p38 activation blocked caspase activation and apoptosis. In a xenograft assay, combination with PA and IR delayed tumor growth by 11.4 days compared with controls, yielding an enhancement factor of 1.48. Collectively, these results indicate that PA functions as a radiosensitizer by enhancing apoptosis through activation of a ROS/p38/caspase pathway and suppression of ERK.
Insights
A natural compound, PA, acts as a potent radiosensitizer for non-small cell lung cancer. It enhances radiation therapy
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality.
- Development of effective radiosensitizers is crucial for improving NSCLC treatment outcomes.
- Natural products offer a promising source for novel therapeutic agents.
Purpose of the Study:
- To identify and characterize a novel radiosensitizer from a natural product library for NSCLC treatment.
- To elucidate the molecular mechanisms underlying the radiosensitizing effect of the identified compound.
- To evaluate the in vivo efficacy of the radiosensitizer in combination with radiation therapy.
Main Methods:
- Screening of a natural product library for cytotoxic compounds against NCI-H460 NSCLC cells.
- Determination of the half-maximal inhibitory concentration (IC₅₀) of the lead compound, PA.
- Assessment of radiosensitizing effects using clonogenic and cell-counting assays.
- Investigation of intracellular mechanisms via immunoblotting, propidium iodide uptake, and reactive oxygen species (ROS) generation assays.
- Evaluation of in vivo radiosensitizing activity in a nude mouse xenograft model.
Main Results:
- PA exhibited cytotoxicity toward NCI-H460 cells with an IC₅₀ of 12 nM.
- PA significantly enhanced radiation-induced cell death, with a dose-enhancement ratio of 1.67.
- Combination therapy increased ROS production, leading to p38 MAPK phosphorylation, ERK signaling suppression, and caspase activation.
- Inhibition of ROS or p38 blocked downstream caspase activation and apoptosis.
- In vivo studies showed that PA combined with IR delayed tumor growth by 11.4 days.
Conclusions:
- PA functions as an effective radiosensitizer for non-small cell lung cancer.
- The radiosensitizing mechanism involves ROS generation, p38 MAPK activation, ERK suppression, and subsequent apoptosis induction.
- PA holds potential as a therapeutic agent to enhance radiation therapy efficacy in NSCLC.
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