Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells

Eyvani, Haniyeh; Moghaddaskho, Farima; Kabuli, Majid; Zekri, Ali; Momeny, Majid; Bazzaz, Javad Tavakkoly; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H.

doi:10.1016/j.lfs.2016.10.020

Cited by 30 publications

(25 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies showed ATO treatment induced G1/S and G2/M cell cycle arrests in cancer cells 18 - 21 . We found ATO induced G2/M cell cycle arrest in ESCC KYSE-150 Cells (Figure 1 A).…”

Section: Resultsmentioning

confidence: 91%

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Zhu¹,

Li²,

Li³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Arsenic trioxide (ATO) is widely studied for its antitumor efficacy and several recent studies suggested the immune modulatory effects of ATO in animal models. In this study we found ATO treatment induced increased ROS production and DNA damage in esophageal squamous cell carcinoma (ESCC) cells, led to DNA damage mediated degradation of Cyclin D1 and upregulation of PD-L1 in these cancer cells. Mechanistically, we found ATO induced a transient upregulation and nuclear translocation of Cyclin D1 by sumoylation. Followed with increased ubiquitination and degradation of Cyclin D1 through T286 phosphorylation, and at least partly mediated by Stat1 Y701 phosphorylation. We observed inversed correlations between Cyclin D1 and PD-L1 expression levels in human ESCC tissues. With 4NQO induced PD-L1 humanized mouse oral and esophageal squamous carcinoma model, we found combinatory administration of ATO and check point inhibitor resulted in a significant reduction of tumor volumes. Inversed correlation between Cyclin D1 with PD-L1 was also observed in the 4NQO induced mouse ESCC and OSCC model. Together, these data suggested ATO induced degradation of Cyclin D1 and functional suppression of CDK4/6 pathway sensitized OSCC and ESCC to checkpoint inhibitor treatment.

show abstract

“…Previous studies showed ATO treatment induced G1/S and G2/M cell cycle arrests in cancer cells 18 - 21 . We found ATO induced G2/M cell cycle arrest in ESCC KYSE-150 Cells (Figure 1 A).…”

Section: Resultsmentioning

confidence: 91%

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Zhu¹,

Li²,

Li³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

show abstract

“…We have previously demonstrated that only a high dose of ATO (> 2 mM) directly increases ROS production and induces apoptosis in myocytes (Zhao et al, 2008). Overwhelming reports have suggested that ATO is not limited to the treatment of leukemia, but has also the potential to suppress solid tumors such as breast cancer, hepatocellular carcinoma, and CRC (Rollig and Illmer, 2009;Wang et al, 2014;Eyvani et al, 2016;Yoon et al, 2016;Shi et al, 2017). The mechanism of ATO-induced apoptosis is mainly ascribed to ROS over-generation.…”

Section: Discussionmentioning

confidence: 99%

Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis

et al. 2020

View full text Add to dashboard Cite

Arsenic trioxide (ATO) is an effective therapeutic agent against acute promyelocytic leukemia (APL); however, its anti-tumor effect on solid tumors such as colorectal cancer (CRC) is still in debate. Ascorbic acid (AA) also produces a selective cytotoxic activity against tumor cells. Here, we exploit the potential benefit of ATO/AA combination in generating cytotoxicity to CRC cells, which may lay the groundwork for the potential combinational chemotherapy of CRCs. According to the results, we found that ATO and AA effectively inhibited the viability of human CRC cells in a synergistic manner. AA and ATO corporately activated caspase-3 to trigger apoptosis and upregulated the expression of caspase-1 and promoted formation of inflammasomes to induce pyroptosis. Furthermore, the stimulation of reactive oxygen species (ROS) overproduction was demonstrated as a subcellular mechanism for apoptosis and pyroptosis induced by ATO/AA combination treatment. Our findings suggest that ATO combination with a conventional dosage of AA offers an advantage for killing CRC cells. The synergistic action of ATO/AA combination might be considered a plausible strategy for the treatment of CRC and perhaps other solid tumors as well.

show abstract

“…In addition, the combination of ATO/VPA also induced G2/M-phase arrest in both cell lines. ATO is known to induce G1 or G2/M-phase arrest depending on cell type [14,36,37]. Similarly, VPA can induce G1 or G2/M-phase arrest in glioblastoma, cervical cancer, and gastric cancer cells [31,38,39].…”

Section: Discussionmentioning

confidence: 99%

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

Park

Han

Park

2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells

Cited by 30 publications

References 44 publications

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma

Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis

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

Contact Info

Product

Resources

About