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Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death

Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, 20 Geonji-ro, Deokjin-gu, Jeonju, Jeollabuk 54907, Korea
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072649
Received: 26 February 2020 / Revised: 3 April 2020 / Accepted: 9 April 2020 / Published: 10 April 2020
(This article belongs to the Section Molecular Oncology)
Arsenic trioxide (ATO; As2O3) has anti-cancer effects in various solid tumors as well as hematological malignancy. Valproic acid (VPA), which is known to be a histone deacetylase inhibitor, has also anti-cancer properties in several cancer cells including lung cancer cells. Combined treatment of ATO and VPA (ATO/VPA) could synergistically enhance anti-cancer effects and reduce ATO toxicity ATO. In this study, the combined anti-cancer effects of ATO and VPA (ATO/VPA) was investigated in NCI-H460 and NCI-H1299 lung cancer cells in vitro and in vivo. A combination of 3 μM ATO and 3 mM VPA (ATO/VPA) strongly inhibited the growths of both lung cancer cell types. DNA flow cytometry indicated that ATO/VPA significantly induced G2/M-phase arrest in both cell lines. In addition, ATO/VPA strongly increased the percentages of sub-G1 cells and annexin V-FITC positive cells in both cells. However, lactate dehydrogenase (LDH) release from cells was not increased in ATO/VPA-treated cells. In addition, ATO/VPA increased apoptosis in both cell types, accompanied by loss of mitochondrial membrane potential (MMP, ∆Ψm), activation of caspases, and cleavage of anti-poly ADP ribose polymerase-1. Moreover, a pan-caspase inhibitor, Z-VAD, significantly reduced apoptotic cell death induced by ATO/VPA. In the xenograft model, ATO/VPA synergistically inhibited growth of NCI-H460-derived xenograft tumors. In conclusion, the combination of ATO/VPA effectively inhibited the growth of lung cancer cells through G2/M-phase arrest and apoptotic cell death, and had a synergistic antitumor effect in vivo. View Full-Text
Keywords: arsenic trioxide; valproic acid; lung cancer cells; cell cycle arrest; apoptosis arsenic trioxide; valproic acid; lung cancer cells; cell cycle arrest; apoptosis
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MDPI and ACS Style

Park, H.K.; Han, B.R.; Park, W.H. Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death. Int. J. Mol. Sci. 2020, 21, 2649. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072649

AMA Style

Park HK, Han BR, Park WH. Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death. International Journal of Molecular Sciences. 2020; 21(7):2649. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072649

Chicago/Turabian Style

Park, Hyun K.; Han, Bo R.; Park, Woo H. 2020. "Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death" Int. J. Mol. Sci. 21, no. 7: 2649. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072649

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