Podophyllotoxin acetate enhances γ-ionizing radiation-induced apoptotic cell death by stimulating the ROS/p38/caspase pathway

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie
Jae Yeon ChoiJong Kuk Park

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....Continue Reading

References

May 8, 2001·International Journal of Cancer. Journal International Du Cancer·I V FilippovichJ F Chatal
Mar 16, 2002·The Cancer Journal·Vinay K GuptaRalph R Weichselbaum
Apr 23, 2004·Trends in Molecular Medicine·James M Olson, Andrew R Hallahan
Aug 11, 2004·Toxicon : Official Journal of the International Society on Toxinology·M GordalizaM A Gómez-Zurita
Jun 15, 2007·Toxicologic Pathology·Susan Elmore
Feb 22, 2008·CA: a Cancer Journal for Clinicians·Ahmedin JemalMichael J Thun
May 29, 2008·Journal of the National Cancer Institute·Brian D LawendaJeffrey B Blumberg
Mar 3, 2009·International Journal of Radiation Oncology, Biology, Physics·David KatzFei-Fei Liu
Jul 25, 2009·Nature Reviews. Cancer·Erwin F Wagner, Angel R Nebreda
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Mar 25, 2011·Nature Reviews. Cancer·Adrian C BeggConchita Vens
Feb 27, 2013·Nature Reviews. Clinical Oncology·Tetsuya MitsudomiYasushi Yatabe
Dec 19, 2013·Genes & Cancer·Anupama Munshi, Rajagopal Ramesh

❮ Previous
Next ❯

Citations

Dec 17, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jeong Hyun ChoJong Kuk Park
Dec 5, 2018·Reviews on Environmental Health·Lei Jiang, Hitoshi Iwahashi
Mar 9, 2019·Journal of Bioenergetics and Biomembranes·Seyed Jalal HosseinimehrHossein Asgarian-Omran
Dec 15, 2020·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·R Pascual-SerraR Sánchez-Prieto
Aug 28, 2021·Frontiers in Cell and Developmental Biology·Hua-Yang FanXin-Hua Liang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis