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Breast cancer decitabine

Ameet K Mishra, Annelie Abrahamsson, Charlotta Dabrosin
The estrogen receptor-alpha (ERα) is used as a predictive marker for anti-estrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ERα can be targeted at the receptor level using the receptor modulator tamoxifen or by the pure anti-estrogen fulvestrant. The role of the second ER, ER-beta (ERβ), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ERα+/ERβ+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ERα-/ERβ+ breast cancer...
July 28, 2016: Oncotarget
Krista P Terracina, Laura J Graham, Kyle K Payne, Masoud H Manjili, Annabel Baek, Sheela R Damle, Harry D Bear
Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model...
September 2016: Cancer Immunology, Immunotherapy: CII
Mélodie Grandin, Pauline Mathot, Guillaume Devailly, Yannick Bidet, Akram Ghantous, Clementine Favrot, Benjamin Gibert, Nicolas Gadot, Isabelle Puisieux, Zdenko Herceg, Jean-Guy Delcros, Agnès Bernet, Patrick Mehlen, Robert Dante
In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so-called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro-apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation-dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin-1 dependence receptor pro-apoptotic pathway...
2016: EMBO Molecular Medicine
Jessica N Haladyna, Taylor Pastuer, Simone S Riedel, Anne-Laure Perraud, Kathrin M Bernt
Transient potential receptor melastatin-2 (TRPM2) is a nonselective cationic, Ca(2+)-permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage and modulates signaling pathways converging into NF-kB. This is of potential interest for acute myeloid leukemia (AML) therapy, as NF-κB signaling is emerging as a key pathway, mediating drug resistance and leukemia-initiating cell survival in AML. Inhibition of NF-κB signaling has been found to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared with normal bone marrow, with the highest levels in the FAB M3-6 subtypes...
July 2016: Experimental Hematology
Michelle L Stewart, Pablo Tamayo, Andrew J Wilson, Stephanie Wang, Yun Min Chang, Jong W Kim, Dineo Khabele, Alykhan F Shamji, Stuart L Schreiber
Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells...
July 15, 2015: Cancer Research
Dong-Xu He, Yu-Dong Xia, Xiao-Ting Gu, Jian Jin, Xin Ma
Although chemotherapy is widely used to treat human cancers, most chemotherapeutic agents only benefit a small fraction of patients because of the heterogeneity of cancers. Therefore, identifying of the sensitivity of cancers toward various chemotherapies would be important for choosing of chemotherapeutic regime. In this study, a 23-gene chemoresistance signature was developed from chemoresistant breast cancers. Functions of the genes in the signature were related with transcription and translation. The signature was indicative of chemoresistance and associated with poor prognosis in multiple chemotherapeutic agents and cancer types...
January 2015: Journal of Pharmaceutical and Biomedical Analysis
Shi-Yong Li, Rong Sun, Hong-Xia Wang, Song Shen, Yang Liu, Xiao-Jiao Du, Yan-Hua Zhu, Wang Jun
Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy...
May 10, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Hong-Xue Wu, Shi-Lun Tong, Chong Wu, Wei-Xing Wang
OBJECTIVES: To explore HtrA1 gene expression and its regulation in human gastric cancers. METHODS: The HtrA1 mRNA levels were examined by QPCR analysis and confirmed its expression with Northern blot analysis. The HtrA1 protein levels in all six gastric epithelial cell lines were investigated by Western blot analysis. Gene copy number was accessed and then sequenced the coding region from each mRNA in all six cell lines. The HtrA1 promoter region DNA methylation status was detected by using bisulfite sequencing analysis...
October 2014: Asian Pacific Journal of Tropical Medicine
Lei Cao, Hua Gao, Ping Li, Songbai Gui, Yazhuo Zhang
Although an antiestrogen treatment for estrogen-dependent diseases, such as breast cancers, has been reported, the effect of this endocrine therapy on prolactinomas and its possible mechanism are unclear. This study investigates the antitumor effect of fulvestrant, which is a new estrogen receptor antagonist, on rat prolactinoma MMQ cells and the possible roles of the Wnt/β-catenin signaling pathway that is involved in this antitumor effect. To investigate the antitumor effect of fulvestrant, the effects of exposure to gradient doses of fulvestrant (0, 0...
June 2014: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Sahra Borges, Heike Döppler, Edith A Perez, Cathy A Andorfer, Zhifu Sun, Panos Z Anastasiadis, E Thompson, Xochiquetzal J Geiger, Peter Storz
INTRODUCTION: DNA methylation-induced silencing of genes encoding tumor suppressors is common in many types of cancer, but little is known about how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes protein kinase D1 (PKD1), a serine/threonine kinase that is expressed in cells of the normal mammary gland, where it maintains the epithelial phenotype by preventing epithelial-to-mesenchymal transition. METHODS: The status of PRKD1 promoter methylation was analyzed by reduced representation bisulfite deep sequencing, methylation-specific PCR (MSP-PCR) and in situ MSP-PCR in invasive and noninvasive breast cancer lines, as well as in humans in 34 cases of "normal" tissue, 22 cases of ductal carcinoma in situ, 22 cases of estrogen receptor positive, HER2-negative (ER+/HER2-) invasive lobular carcinoma, 43 cases of ER+/HER2- invasive ductal carcinoma (IDC), 93 cases of HER2+ IDC and 96 cases of triple-negative IDC...
2013: Breast Cancer Research: BCR
Francescopaolo Di Cello, Leslie Cope, Huili Li, Jana Jeschke, Wei Wang, Stephen B Baylin, Cynthia A Zahnow
Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA)...
2013: PloS One
Kareem I Batarseh
In a previous work, the author has investigated the antimicrobial and cytotoxic properties of tartaric and glutamic acids silver(I) chelates. In a following work, the author has reported on the in vitro cytotoxicity and the mechanism of action of a silver(I) tartaric acid chelate synthesized by the author given the title name Aliargentumycine (AAgM) on hematopoietic malignancies. The in vitro antineoplastic activities of AAgM on solid human breast ductal carcinoma (T- 47D) and disseminated T-cell acute lymphoblastic leukemia (Jurkat) cell lines, its mechanism of action and its structural properties were investigated here...
2013: Current Medicinal Chemistry
Sivakumar Vijayaraghavalu, Vinod Labhasetwar
DNA methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1 depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly enhanced antiproliferative effect of DAC...
April 30, 2013: Cancer Letters
Sivakumar Vijayaraghavalu, Josephine Kamtai Dermawan, Venugopalan Cheriyath, Vinod Labhasetwar
Epigenetic alterations such as aberrant DNA methylation and histone modifications contribute substantially to both the cause and maintenance of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Our hypothesis is that treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes...
January 7, 2013: Molecular Pharmaceutics
J C Sousa, R T Germano, C C M Castro, S M M Magalhaes, R F Pinheiro
Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation...
2012: Genetics and Molecular Research: GMR
Simon J Cooper, Christina A von Roemeling, Kylie H Kang, Laura A Marlow, Stefan K Grebe, Michael E Menefee, Han W Tun, Gerardo Colon-Otero, Edith A Perez, John A Copland
Metastatic solid tumors are aggressive and mostly drug resistant, leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple-negative breast cancer (TNBC). Therefore, the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the U.S. Food and Drug Administration for the treatment of various hematologic malignancies...
October 2012: Molecular Cancer Therapeutics
Sivakumar Vijayaraghavalu, Chiranjeevi Peetla, Shan Lu, Vinod Labhasetwar
In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype...
September 4, 2012: Molecular Pharmaceutics
Hsing-Chen Tsai, Huili Li, Leander Van Neste, Yi Cai, Carine Robert, Feyruz V Rassool, James J Shin, Kirsten M Harbom, Robert Beaty, Emmanouil Pappou, James Harris, Ray-Whay Chiu Yen, Nita Ahuja, Malcolm V Brock, Vered Stearns, David Feller-Kopman, Lonny B Yarmus, Yi-Chun Lin, Alana L Welm, Jean-Pierre Issa, Il Minn, William Matsui, Yoon-Young Jang, Saul J Sharkis, Stephen B Baylin, Cynthia A Zahnow
Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells...
March 20, 2012: Cancer Cell
Ferda Ari, Rudolf Napieralski, Engin Ulukaya, Egemen Dere, Christoph Colling, Katja Honert, Achim Krüger, Marion Kiechle, Manfred Schmitt
Epigenetic drugs are promising add-ons to cancer treatment; still, adverse effects concerning tumour promotion have been reported occasionally. In this in vitro study, we investigated the effect of combination treatment of decitabine with anthracycline-based chemotherapy [5-fluorouracil plus epirubicine plus cyclophosphamide (FEC)] on viability and metastatic activity of breast cancer cell lines, MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive). The effect of decitabine and its combined treatment with FEC on viability of both cancer cell lines was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide and adenosine triphosphate (ATP) cell survival assays...
December 2011: Cell Biochemistry and Function
Min-Yu Chen, Warren S-L Liao, Zhen Lu, William G Bornmann, Violeta Hennessey, Michele N Washington, Gary L Rosner, Yinhua Yu, Ahmed Ashour Ahmed, Robert C Bast
BACKGROUND: Epigenetic therapy has had a significant impact on the management of hematologic malignancies, but its role in the treatment of ovarian cancer remains to be defined. The authors previously demonstrated that treatment of ovarian and breast cancer cells with DNA methyltransferase and histone deacetylase (HDAC) inhibitors can up-regulate the expression of imprinted tumor suppressors. In this study, demethylating agents and HDAC inhibitors were tested for their ability to induce re-expression of tumor suppressor genes, inhibiting growth of ovarian cancer cells in culture and in xenografts...
October 1, 2011: Cancer
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