Abstract
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 G2-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 EGFR-mediated 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.
Highlights
In 2000, arsenic trioxide (ATO; Fig. 1A) was approved by the U.S Food and Drug Administration for the treatment of relapsed and refractory acute promyelocytic leukemia (APL; ref. 1) and, represents besides platinum compounds the only metal-based anticancer drug in clinical use
Besides the development of new therapeutic approaches, one of the most promising options to improve treatment efficacy is the use of combination strategies [39]
Some recent reports indicate that exposure to inorganic arsenic salts leads to activation of EGF receptor (EGFR) in nonmalignant as well as in malignant cells, for example, via c-Src kinase-mediated signals [14,15,16,17,18,19]
Summary
In 2000, arsenic trioxide (ATO; Fig. 1A) was approved by the U.S Food and Drug Administration for the treatment of relapsed and refractory acute promyelocytic leukemia (APL; ref. 1) and, represents besides platinum compounds the only metal-based anticancer drug in clinical use. On the basis of its successful clinical application, the anticancer activity of ATO either as monotreatment or in combination with other agents was intensively studied in various other hematologic malignancies [5, 6] and several solid cancer types [7]. 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]. 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
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