Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial

Lin, Chia‐Chi; Hsu, Chiun; Hsu, Chih-Hung; Hsu, Wei-Li; Cheng, Ann‐Lii; Yang, James Chih‐Hsin

doi:10.1007/s10637-006-9004-9

Cited by 117 publications

(87 citation statements)

References 23 publications

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“…The anticancer activity of arsenic is well known and resulted in the recent approval of ATO against APL (1). However, the activity of ATO against solid cancer types is so far rather limited (8)(9)(10)(11)40). Some recent reports indicate that exposure to inorganic arsenic salts leads to activation of EGFR in nonmalignant as well as in malignant cells, for example, via c-Src kinase-mediated signals (14)(15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of its successful clinical application, the anticancer activity of ATO either as monotreatment or in combination with other agents was also intensively studied in various other hematologic malignancies (5,6) and several solid cancer types (7). However, reports from phase II clinical trials on patients with hepatocellular carcinoma (HCC), metastatic renal cell carcinoma, and metastatic melanoma suggested so far that ATO has only limited efficacy against solid tumors (8)(9)(10)(11)(12). Although multiple resistance mechanisms for arsenic have been described on the cellular level (1), the reasons underlying the lack of efficacy of ATO in solid tumor types are still widely unclear.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Promising in vitro effects of ATO on gastric cancer (8), HNSCC (9), neuroblastoma (10), esophageal (11), prostate and ovarian carcinomas (12) have been reported. Furthermore, Phase II studies of ATO in patients with relapsed or refractory multiple myeloma (13), metastatic melanoma (14), hepatocellular carcinoma (15) and myelodysplatic syndromes (16) have been carried out.…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide enhances the cytotoxic effect of cisplatin in head and neck squamous cell carcinoma cell lines

et al. 2012

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“…Previously, it has also been used in therapy for solid tumors such as HCC, gastric cancer, colorectal cancer, and renal cancer (18)(19)(20). Although a significant anti-cancer effect had been reported in preclinical and clinical trials, failure of chemotherapy was reported frequently in patients and some cell lines (5). Among the reasons anti-cancer drugs fail, the most common is acquired drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Years before the noticeable anti-cancer activity of arsenic trioxide attracted the attention of oncologists, the effective therapeutic results in vitro and in vivo were surprising. However, recently a phase II trial evaluating the efficacy and toxicity of arsenic trioxide in patients with HCC showed that single-agent arsenic trioxide is pool active against advanced HCC (5). Although several likely factors could explain the inefficacy of arsenic trioxide against advanced HCC, the appearance of drug resistance might be an important possibility.…”

Section: Introductionmentioning

confidence: 99%

The overexpression of multidrug resistance-associated proteins and gankyrin contribute to arsenic trioxide resistance in liver and gastric cancer cells

Chen

Zhang²,

Liu³

2009

Oncol Rep

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Abstract. Arsenic trioxide has been used as a therapeutic agent for acute promyelocytic leukemia and recently for some solid tumors. Although arsenic trioxide has been shown to significantly inhibit the growth of solid tumor cells in vitro, clinical trials indicate that arsenic trioxide alone is pool active against non-hematologic malignant diseases. To understand the mechanisms of arsenic resistance in solid tumor cells, we established two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, isolated from human liver cancer cell line HepG2 and human gastric cancer cell line SGC7901, respectively, by a series of stepwise selections via treatment with increasing concentrations of arsenic trioxide. Three ABC transporter proteins, ABCB1, ABCC1 and ABCC2, were expressed increasingly and differently in two arsenic-resistant cell lines. Further, tumor suppressor p53 was overexpressed in two arsenic-resistant cell lines, but the levels of p53 mediators MDM2 and gankyrin, which regulate the ubiquitination of p53, increased simultaneously. In addition, an increase in the phosphorylation of Rb at Ser795 in the two cell lines might also result from the presence of MDM2 and gankyrin, which suggest that the inactivation of p53 and Rb contribute to drug resistance. These two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, may be useful for studying the mechanism of arsenic resistance in solid tumors and may provide a way to overcome it.

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Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial

Abstract: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC.

Cited by 117 publications

References 23 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 enhances the cytotoxic effect of cisplatin in head and neck squamous cell carcinoma cell lines

The overexpression of multidrug resistance-associated proteins and gankyrin contribute to arsenic trioxide resistance in liver and gastric cancer cells

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