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

Abstract

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.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…Arsenicinduced expression reductions in DNMT1 and DNMT3A, as well as in SAM abundance, were observed in the human HaCaT cell line (a spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin) [236]. Arsenic trioxide used in chemotherapy [289,290] was shown to induce DNA hypomethylation in a human colon cancer reporter system at 50 and 10 µM after 24 h or 72 h, respectively [291]. In the human bronchial epithelial SV-40 immortalised cell line (BEAS-2B) exposed to arsenic for 8 weeks, reduction in mRNA and protein expressions of DNMT1, 3A, and 3B, were associated to a reduction in CTCF binding-protein on the DNMT promoters [240].…”

Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment

“…The combination therapy of VPA and simvastatin sensitized prostate cancer cells via YAP inhibition (6). VPA and Arsenic Trioxide were verified to induce cell-cycle arrest at the G2/M phase and apoptotic cell death in lung cancer (88). Moreover, VPA could also enhance anti-PD-L1 tumor immunotherapy in blocking myeloid-derived suppressor cell function (89).…”

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

“…Valproic acid (VPA; Fig. 12 , 79 ) inhibits histone deacetylase to reduce cancer cell proliferation and induce apoptosis, as well as inducing differentiation and inhibiting angiogenesis in cancer 96 . Antidepressants mainly inhibit reuptake of amine neurotransmitters, but their antitumor mechanism are more complicated, and more effort should be required for drug repurposing.…”