{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:18:11Z","timestamp":1771460291549,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T00:00:00Z","timestamp":1586476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1I1A2A01041209"],"award-info":[{"award-number":["2019R1I1A2A01041209"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03bcM 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, \u2206\u03a8m), 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.<\/jats:p>","DOI":"10.3390\/ijms21072649","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T04:45:31Z","timestamp":1586753131000},"page":"2649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2\/M-Phase Arrest and Apoptotic Cell Death"],"prefix":"10.3390","volume":"21","author":[{"given":"Hyun Kyung","family":"Park","sequence":"first","affiliation":[{"name":"Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, 20 Geonji-ro, Deokjin-gu, Jeonju, Jeollabuk 54907, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo Ram","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, 20 Geonji-ro, Deokjin-gu, Jeonju, Jeollabuk 54907, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, 20 Geonji-ro, Deokjin-gu, Jeonju, Jeollabuk 54907, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.21037\/jtd.2018.03.15","article-title":"Updated statistics of lung and bronchus cancer in United States (2018)","volume":"10","author":"Boloker","year":"2018","journal-title":"J. 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