Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide

Sertel, Serkan; Tome, Margaret E.; Briehl, Margaret M.; Bauer, Judith; Hock, Kai; Plinkert, Peter K.; Efferth, Thomas

doi:10.1371/journal.pone.0035584

Cited by 21 publications

(17 citation statements)

References 64 publications

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“…Despite the fact that BCRP is known to mediate concurrent resistance to chemotherapeutic agents including mitoxantrone, doxorubicin, and daunorubicin in MCF-7/AdrVp, a multidrugresistant human breast cancer subline (54), its relevance for resistance to arsenic is unknown. By demonstrating the enhanced As[i] along with the synergistic cytotoxicity in MCF-7 cells when treated with As III combined with Ko134, this suggests for the first time the possibility of manipulating BCRP to overcome the resistance to the arsenic-based regimens, although a previous study reported that BCRPoverexpressing MDA-MB-231-BCRP cells were not more resistant to As III than their drug-sensitive counterparts (55). Therefore, further studies need to be launched in order to draw a solid conclusion about the involvement of BCRP in arsenic resistance.…”

Section: Discussionmentioning

confidence: 96%

Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7

Yao

Yuan

Wang

et al. 2017

International Journal of Oncology

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To provide novel insight into the development of new therapeutic strategies to combat breast cancer using trivalent arsenic (AsIII)-based combination therapy, the cytotoxicity of a combination of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, was investigated in the human breast cancer cell line MCF-7. Cytotoxicity was evaluated using cell viability, colony formation, wound healing, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes associated with cell proliferation and death were analyzed using real-time PCR and western blotting. Intracellular arsenic accumulation (As[i]) was also determined. Tetra significantly enhanced the cytotoxicity of AsIII in MCF-7 cells in a synergistic manner. The combined treatment upregulated the expression level of FOXO3a, and subsequently resulted in a concomitant increase in the expression levels of p21, p27, and decrease of cycline D1, which occurred in parallel with G0/G1 phase arrest. Autophagy induction was also observed in the combination treatment. Importantly, combining AsIII with Tetra exhibited a synergistic inhibitory effect on the expression level of survivin. Furthermore, enhanced As[i] along with synergistic cytotoxicity was observed in MCF-7 cells treated with AsIII combined with Tetra or Ko134, an inhibitor of breast cancer resistance protein (BCRP), suggesting that Tetra or the BCRP inhibitor probably intervened in the occurrence of resistance to arsenic therapy by enhancing the As[i] via modulation of multidrug efflux transporters. These results may provide a rational molecular basis for the combination regimen of AsIII plus Tetra, facilitating the development of AsIII-based anticancer strategies and combination therapies for patients with solid tumors, especially breast cancer.

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Section: Discussionmentioning

confidence: 96%

Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7

Yao

Yuan

Wang

et al. 2017

International Journal of Oncology

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“…As one potential mechanism, upregulation of protective anti-oxidative enzymes which has been associated with CDDP resistance [45], [46] as well as resistance to arsenicals [47] might be involved in the observed cross-resistance.…”

Section: Discussionmentioning

confidence: 99%

Increased Growth-Inhibitory and Cytotoxic Activity of Arsenic Trioxide in Head and Neck Carcinoma Cells with Functional p53 Deficiency and Resistance to EGFR Blockade

et al. 2014

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Background and PurposeMutations in the p53 gene are frequently observed in squamous cell carcinoma of the head and neck region (SCCHN) and have been associated with drug resistance. The potential of arsenic trioxide (ATO) for treatment of p53-deficient tumor cells and those with acquired resistance to cisplatin and cetuximab was determined.Material and MethodsIn a panel of 10 SCCHN cell lines expressing either wildtype p53, mutated p53 or which lacked p53 by deletion the interference of p53 deficiency with the growth-inhibitory and radiosensitizing potential of ATO was determined. The causal relationship between p53 deficiency and ATO sensitivity was evaluated by reconstitution of wildtype p53 in p53-deficient SCCHN cells. Interference of ATO treatment with cell cycle, DNA repair and apoptosis and its efficacy in cells with acquired resistance to cisplatin and cetuximab was evaluated.ResultsFunctional rather than structural defects in the p53 gene predisposed tumor cells to increased sensitivity to ATO. Reconstitution of wt p53 in p53-deficient SCCHN cells rendered them less sensitive to ATO treatment. Combination of ATO with irradiation inhibited clonogenic growth in an additive manner. The inhibitory effect of ATO in p53-deficient tumor cells was mainly associated with DNA damage, G2/M arrest, upregulation of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors and apoptosis. Increased activity of ATO was observed in cetuximab-resistant SCCHN cells whereas cisplatin resistance was associated with cross-resistance to ATO.ConclusionsAddition of ATO to treatment regimens for p53-deficient SCCHN and tumor recurrence after cetuximab-containing regimens might represent an attractive strategy in SCCHN.

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“…During the past years, this concept provided a fertile ground to unravel mechanisms of action of new drugs and to use gene expression profiles for the prediction of chemosensitivity of tumor cells [54–56]. We applied this approach to gain insight of determinants of activity of natural products derived from traditional Chinese medicine, for example, homoharringtonine, artemisinin, cantharidin, arsenic trioxide, and others [36–40, 57]. …”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic Activity and Pharmacogenomics of Medicinal Plants from Traditional Korean Medicine

Seo

Kuete

Kadioglu

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Aim. In the present study, we investigated the antiangiogenic properties of 59 plants used in traditional Korean medicine. Selected phytochemicals were investigated in more detail for their modes of action. Methods. A modified chicken-chorioallantoic-membrane (CAM) assay using quail eggs was applied to test for antiangiogenic effects of plant extracts. A molecular docking in silico approached the binding of plant constituents to the vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2). Microarray-based mRNA expression profiling was employed to correlate the 50% inhibition concentrations (IC50) of a panel of 60 NCI cell lines to these phytochemicals. Results. Extracts from Acer mono leaves, Reynoutria sachalniensis fruits, Cinnamomum japonicum stems, Eurya japonica leaves, Adenophora racemosa whole plant, Caryopteris incana leaves-stems, and Schisandra chinensis stems inhibited angiogenesis more than 50% in quail eggs. Selected phytochemicals from Korean plants were analyzed in more detail using microarray-based mRNA expression profiles and molecular docking to VEGFR1 and VEGFR2. These results indicate multifactorial modes of action of these natural products. Conclusion. The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.

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Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide

Cited by 21 publications

References 64 publications

Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7

Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7

Increased Growth-Inhibitory and Cytotoxic Activity of Arsenic Trioxide in Head and Neck Carcinoma Cells with Functional p53 Deficiency and Resistance to EGFR Blockade

Antiangiogenic Activity and Pharmacogenomics of Medicinal Plants from Traditional Korean Medicine

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