Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells

Martı́n, Vanesa; Sánchez‐Sánchez, Ana M.; Herrera, Federico; Gomez-Manzano, Candelaria; Fueyo, Juan; Álvarez-Vega, Marco; Antolı́n, Isaac; Rodríguez, Carmen

doi:10.1038/bjc.2013.188

Cited by 113 publications

(97 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that demethylation of the ABCG2 promoter is related to reactivation of the gene and the subsequent ABCG2-dependent MDR phenotype (26,45). To this end, drug-induced epigenetic modulation of the ABCG2 gene has attracted increasing attention recently (45)(46)(47). Our data showed for the first time that afatinib induced methylation of the ABCG2 promoter, thus leading to a decrease in mRNA level of ABCG2 in S1-MI-80 cells, which has not been reported with other TKIs.…”

Section: Discussionmentioning

confidence: 99%

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Wang

et al. 2014

Cancer Research

View full text Add to dashboard Cite

Cancer stem cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence that they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ATP-binding cassette subfamily G member 2 (ABCG2) confers chemoresistance to CSCs, where it serves as a potential biomarker and therapeutic target. Here, we show that afatinib, a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4, preferentially eliminated side population cells with CSC character, in both cell lines and patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells, afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA-damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome, or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication. Cancer Res; 74(16); 4431-45. Ó2014 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Wang

et al. 2014

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Martin and colleagues observed that melatonin markedly increased the cancer killing activity of temozolomide, doxorubicin or mitoxantrone [18]. Their study indicated that co-incubation of melatonin plus a chemotherapeutic drug resulted in a synergistic inhibitory action in the three BTSC lines (NSC23, NSC7-2 and NSC11) tested.…”

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

“…Thus, a therapeutic strategy that targets both the tumor bulk and the brain tumor stem cell (BTSC) compartment is essential to bring about a stable and enduring remission [18].…”

Section: The Impact Of Melatonin On Tumor Stem Cells Melatonin Inhibimentioning

confidence: 99%

“…This molecule executes its anticancer effects in various types of cancer due to its pro-apoptotic, anti-proliferative, anti-cell differentiation and anti-angiogenic actions [15,16]. Numerous studies indicate that melatonin inhibits multiple crucial signals associated with brain tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance [17][18][19]. Melatonin not only exhibits an antitumor effects on total tumor mass but also antitumor actions on subpopulations of CSCs [21].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

View full text Add to dashboard Cite

Aim: Cancer stem cells (CSCs) exhibited an excessive migratory and invasive potential. Melatonin may inhibit multiple crucial signals associated with tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance. Carbon ion irradiation may be a promising therapeutic modality in both non-stem-like and stem-like tumor cells in contrast to photon irradiation. A comprehensive understanding of the mechanisms and molecular pathways associated with invasive properties of CSCs is essential in developing novel treatment options for cancer therapy that target CSCs. Materials and methods:A systematic review of the existing literature was conducted using the following search terms: 'melatonin', 'X-ray irradiation', 'charged particle irradiation', 'carbon ion irradiation', 'cancer stem cells', 'tumor-initiating cells' and 'cancer stem-like cells'. The search used PubMed and spanned the period from January 2000 to December 2016. Conclusion:Cancer stem cells possess the capacity of self-renewal and pluripotency, generating all cells within a tumor, and are responsible for tumor growth, therapy resistance and metastasis. Melatonin attenuated AKT activation, EZH2 S21 phosphorylation, EZH2-STAT3 interactions and altered histone modifications to reduce tumor initiation and propagation of brain tumor stem cells (BTSC). Melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and BTSCs through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter. Melatonin treatment induced cell death with ultrastructural characteristics of autophagy. Breast cancer stem cells (BCSCs) are responsive to melatonin treatment by way of reducing the viability and the invasiveness of breast cancer mammospheres as well as regulating the expression of OCT4, N-cadherin and vimentin proteins associated with epithelial mesenchymal transition in BCSCs. Carbon irradiation is effective in brain tumor stem cell (BTSC) elimination with relative biologic effectiveness (RBE) in the range of 1.87-3.44. Carbon ion irradiation may be a promising therapeutic modality because it reduces migration and invasion processes in both head and neck squamous cell carcinoma and cancer stem cells in contrast to photon irradiation. Low LET X-ray irradiation may essentially eradicate the non-stem-like tumor cells, consequently the radioresistant cancer stem-like cell population is obviously enriched. In contrast, carbon ion irradiation may eradicate both non-stemlike and stem-like tumor cells at the same time. Carbon ion irradiation is a promising tool to eradicate putative colon cancer stem-like cells. Further investigation to elucidate the mechanisms and molecular pathways involved in cancer stem cells particularly associated with melatonin and carbon ion irradiation certainly is warranted.

show abstract

“…Quiescence is associated with cancer stem cells, a subpopulation of cancer cells that are critical for tumor progression (24)(25)(26). Tumor stem cells were reported primarily at the status of quiescence (27,28). Differentiation of tumor stem cells may lead to the loss of quiescent status (29,30).…”

Section: Discussionmentioning

confidence: 99%

Pregnancy promotes pituitary tumors by increasing the rate of the cell cycle

Yin¹,

2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Pituitary tumors may secrete hormones that affect pregnancy. Pregnancy also induces pituitary tumor growth; however, how pregnancy increases the growth of pituitary tumors remains unclear. The present study investigated pregnant female mice with subcutaneous pituitary tumors. The time of tumor occurrence and tumor weight were detected in pregnant and control mice. Tumor weights were measured at the end of the experiment. Blood was collected from pregnant and control mice. Brain-derived neurotrophic factor (BDNF) levels in the blood were detected using an ELISA kit. The in vitro effects of BDNF on pituitary tumor AtT-20 cell proliferation and cell cycle were investigated. It was revealed that pregnancy promoted the growth of pituitary tumors. In comparison to non-pregnant mice, the pregnant mice exhibited increased BDNF levels in the blood. In vitro BDNF treatment was able to increase the rate of proliferation of pituitary tumor cells. Additional cell cycle analysis revealed that BDNF was able to alter the cell cycle distribution of pituitary tumor cells. These results indicated that pregnancy was able to increase the BDNF level and promote the growth of pituitary tumor cells by increasing the rate of the cell cycle, leading to increased tumor growth rate in vivo. The present study provides insights into how pregnancy affects the growth of pituitary tumors. Therefore, it may be beneficial to perform pituitary tumor diagnosis or therapy on pregnant patients.

show abstract

Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells

Cited by 113 publications

References 25 publications

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

The impact of melatonin and carbon ion irradiation on cancer stem cells

Pregnancy promotes pituitary tumors by increasing the rate of the cell cycle

Contact Info

Product

Resources

About