Drug Transporter-Mediated Protection of Cancer Stem Cells From Ionophore Antibiotics

Boesch, Maximilian; Zeimet, Alain G.; Rumpold, Holger; Gastl, Guenther; Sopper, Sieghart; Wolf, Dominik

doi:10.5966/sctm.2015-0054

Cited by 30 publications

(23 citation statements)

References 25 publications

(55 reference statements)

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“…Thereafter, reports from Rotin and Margolis had shown that nigericin inhibited DNA synthesis of cancer cells by increasing intracellular pH and causing acidification of cytoplasm (6,7). Recently, nigericin was found to be involved in various types of cancer (8)(9)(10)(11). For example, in 2010, the study of Mashima and colleagues showed that nigericin-like compounds suppressed androgen receptor expression at the mRNA level and could be applied as new-type therapeutic agents in hormone-refractory prostate cancer (12).…”

Section: Introductionmentioning

confidence: 99%

Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/β-catenin Signaling Pathway

Liu

Hua

et al. 2018

Molecular Cancer Therapeutics

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Nigericin, an antibiotic derived from , which works by acting as an H, K, and Pb ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer cells and clarify the underlying mechanism. We exposed two colorectal cancer lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in colorectal cancer cells. The subsequent experiments and implied that nigericin could significantly suppress the tumor growth, migration, and invasion, and induce the apoptosis of colorectal cancer cells. Our results of Western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in colorectal cancer cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin overexpression colorectal cancer cells. Western blot, SuperTOPFlash luciferase reporter, and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anticancer effects on colorectal cancer cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in colorectal cancer progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin toward cancer cells, and suggest possible clinical application in colorectal cancer. .

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Section: Introductionmentioning

confidence: 99%

Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/β-catenin Signaling Pathway

Liu

Hua

et al. 2018

Molecular Cancer Therapeutics

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“…SP fractions derived from ovarian cancer cell lines exhibited marked resistance to cytotoxic agents . Our clinical data demonstrate that exclusively platinum‐refractory cancer specimens showed significantly increased Vav3.1 mRNA levels compared to all other cancers including fully platinum sensitive, PPS and even platinum resistant tumors.…”

Section: Discussionmentioning

confidence: 67%

“…SP fractions derived from ovarian cancer cell lines exhibited marked resistance to cytotoxic agents. 46,47 Our clinical data demonstrate that exclusively platinum-refractory cancer specimens showed significantly increased Vav3.1 mRNA levels compared to all other cancers including fully platinum sensitive, PPS and even platinum resistant tumors. Although, administration of platinum is generally associated with high rates of clinical responses, drug exposure can lead to an adaptive response rendering malignant cells less platinumsusceptible over time.…”

Section: Increased Vav31 Expression In Platinum-refractory Patientsmentioning

confidence: 72%

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

Reimer

Boesch

Wolf

et al. 2017

Intl Journal of Cancer

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Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type-II but not in Type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance.

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“…CSCs 33, 34, 60 and EMT 35, 37, 42, 43 both fuel cancer progression and mediate drug resistance. The transmembranous glycoprotein EpCAM exerts distinct and partially paradoxical functions in CSCs and EMT: while CSCs from epithelial‐derived tumors express high levels of EpCAM, EMT cells have downregulated the expression of this key epithelial denominator.…”

Section: Discussionmentioning

confidence: 99%

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

Boesch

Spizzo

Seeber

2018

Stem Cells Translational Medicine

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Colorectal cancer (CRC) is one of the most common malignancies worldwide. In spite of various attempts to ameliorate outcome by escalating treatment, significant improvement is lacking particularly in the adjuvant setting. It has been proposed that cancer stem cells (CSCs) and the epithelial‐to‐mesenchymal transition (EMT) are at least partially responsible for therapy resistance in CRC. The epithelial cell adhesion molecule (EpCAM) was one of the first CSC antigens to be described. Furthermore, an EpCAM‐specific antibody (edrecolomab) has the merit of having launched the era of monoclonal antibody treatment in oncology in the 1990s. However, despite great initial enthusiasm, monoclonal antibody treatment has not proven successful in the adjuvant treatment of CRC patients. In the meantime, new insights into the function of EpCAM in CRC have emerged and new drugs targeting various epitopes have been developed. In this review article, we provide an update on the role of EpCAM in CSCs and EMT, and emphasize the potential predictive selection criteria for novel treatment strategies and refined clinical trial design. stem cells translational medicine 2018;7:495–501

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Drug Transporter-Mediated Protection of Cancer Stem Cells From Ionophore Antibiotics

Cited by 30 publications

References 25 publications

Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/β-catenin Signaling Pathway

Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/β-catenin Signaling Pathway

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

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