Effect of Arsenic Trioxide on Cell Cycle Arrest in Head and Neck Cancer Cell Line PCI-1

Seol, Jae Goo; Park, Woo H.; Kim, Eun S.; Jung, Chul Won; Hyun, Jung Mi; Kim, Byoung K.; Lee, Young Y.

doi:10.1006/bbrc.1999.1697

Cited by 72 publications

(46 citation statements)

References 25 publications

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“…These results are in accordance with the vitality data, where the drug combination was able to overcome the intrinsic resistance of A549 cells to ATO. This is of interest as there are several reports that ATO induces G 2 -M arrest accompanied by a (p53/p21-dependent) decrease of cyclin B expression (31)(32)(33). Thus, the decrease of cyclin B1 only in the combination samples reflects the resensitization of A549 cells to ATO by erlotinib.…”

Section: Ato Synergizes With Inhibitors Of the Egfr Downstream Signalingmentioning

confidence: 89%

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G 2 -M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFRmediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR. Mol Cancer Ther; 12(6); 1073-84. Ó2013 AACR.

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Section: Ato Synergizes With Inhibitors Of the Egfr Downstream Signalingmentioning

confidence: 89%

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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“…The outcome was more successful than that achieved by treating HCC with As 2 O 3 in combination with the chemotherapeutic agents cisplatin and doxorubucin. 26 Following the discovery of As 2 O 3 as a new and promising treatment for various types of leukemia, particularly APL, a large number of studies have investigated the use of As 2 O 3 in the treatment of solid cancers, including neuroblastoma, 27 head and neck, 28 gastric, 14 transitional cell, 15 prostate 9 and renal cell carcinoma, 29 esophageal, 10 prostate, 11 colorectal 12 and hepatocellular 13,26 cancers. However, the results achieved were not comparable with the previous success obtained with APL.…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide synergizes with B7H3‐mediated immunotherapy to eradicate hepatocellular carcinomas

Luo

Qiao

Meng

et al. 2005

Intl Journal of Cancer

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Arsenic trioxide (As 2 O 3 ), a valuable anticancer drug for the treatment of acute promyelocytic leukemia, may also have therapeutic potential for the treatment of solid tumors. However, its therapeutic efficacy against solid tumors is lacking even at high dosages. Other therapeutic strategies are required to enhance the efficacy of As 2 O 3 against solid tumors such as hepatocellular carcinoma (HCC), which is refractory to chemotherapy. B7H3, a new member of the B7 family, has been shown to induce antitumor immunity. Intratumoral injection of B7H3 plasmids eradicates small EL-4 lymphomas, but monotherapy is ineffective against large tumors. Here we investigated whether As 2 O 3 would synergize with B7H3 immunotherapy to combat HCC. Large subcutaneous H22 HCCs (0.7-0.8 cm in diameter) established in BALB/c mice were rapidly and completely eradicated when intratumoral administration of As 2 O 3 was preceded by in situ gene transfer of B7H3. In contrast, neither As 2 O 3 nor B7H3 monotherapy was effective. The antitumor activity of As 2 O 3 was attributed to increased tumor-cell apoptosis, perhaps as a result of direct cytotoxicity as well as decreased tumor angiogenesis. Combination therapy generated potent systemic antitumor immunity mediated by CD81 and NK cells that was effective in combating a systemic challenge of 1 3 10 7 parental H22 cells. It led to the simultaneous and complete regression of multiple distant tumor nodules, concomitant with increased levels of serum IFN-c and cytotoxic T lymphocyte (CTL) activity. In conclusion, combining B7H3-mediated immunotherapy with As 2 O 3 warrants investigation as a therapeutic strategy to combat HCC, and other malignancies. ' 2005 Wiley-Liss, Inc.

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“…Furthermore, ATO may be active against other malignancies such as solid tumor since the mechanisms of action of ATO are mainly the induction of apoptosis and the cell cycle arrest (14). In fact, accumulating literature has demonstrated that ATO regulate many biological functions of cell proliferation, differentiation and angiogenesis as well as apoptosis in the solid tumor cells of renal (15), head and neck (16), ovarian (17), prostate (17), hepatoma (18), bladder (19), colon (20), lung (21), breast (22), cervical (23) and gastric cancer cells (24). ATO as a mitochondrial poison can induce the failure of the mitochondrial transmembrane potential (MMP; ∆Ψ m ) and, as such, it generates high amounts of ROS (14,25,26).…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

You

Park

2012

Oncology Reports

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Abstract. Arsenic trioxide (ATO; As 2 O 3 ) induces apoptotic cell death in various cancer cells including lung cancer via the induction of reactive oxygen species (ROS). However, little is known about the toxicological effects of ATO on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψ m ). ATO increased ROS levels including O 2•-and GSH depleted cell numbers. NAC attenuated the growth inhibition, death and MMP (∆Ψ m ) loss in ATO-treated HPF cells and also decreased the ROS levels in these cells. However, vitamin C enhanced the growth inhibition, death, MMP (∆Ψ m ) loss and GSH depletion by ATO and even strongly increased mitochondrial O 2•-levels in ATO-treated HPF cells. BSO showed a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth inhibition, cell death, MMP (∆Ψ m ) loss and GSH depletion. Moreover, superoxide dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO, which was not correlated with ROS and GSH level changes. In conclusion, ATO induced the growth inhibition and death of HPF cells, accompanied by increasing ROS levels and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and BSO enhanced the death.

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Effect of Arsenic Trioxide on Cell Cycle Arrest in Head and Neck Cancer Cell Line PCI-1

Cited by 72 publications

References 25 publications

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Arsenic trioxide synergizes with B7H3‐mediated immunotherapy to eradicate hepatocellular carcinomas

Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

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