1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer
| العنوان: | 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
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| المؤلفون: | Stephen Safe, Yunpeng Su, Arthur E. Frankel, Indira Jutooru, Rola Barhoumi, Gayathri Chadalapaka, Kathy Vanderlaag, Robert C. Burghardt |
| المصدر: | BMC Cancer, Vol 10, Iss 1, p 669 (2010) BMC Cancer |
| بيانات النشر: | BMC, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Cancer Research, Indoles, Time Factors, genetic structures, Apoptosis, Amino Acid Chloromethyl Ketones, Mice, chemistry.chemical_compound, 0302 clinical medicine, Caspase, Mice, Inbred BALB C, 0303 health sciences, biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Caspase Inhibitors, Immunohistochemistry, 3. Good health, Proto-Oncogene Proteins c-bcl-2, Receptors, Estrogen, Oncology, Caspases, 030220 oncology & carcinogenesis, Beclin-1, Female, Macrolides, Growth inhibition, Microtubule-Associated Proteins, G1 phase, Research Article, Programmed cell death, Recombinant Fusion Proteins, Blotting, Western, Mice, Nude, Antineoplastic Agents, Breast Neoplasms, Cysteine Proteinase Inhibitors, Transfection, lcsh:RC254-282, Necrosis, 03 medical and health sciences, Cell Line, Tumor, Autophagy, Biomarkers, Tumor, Genetics, Animals, Humans, Cell Proliferation, 030304 developmental biology, L-Lactate Dehydrogenase, Cell growth, Membrane Proteins, Aryl hydrocarbon receptor, Xenograft Model Antitumor Assays, Molecular biology, chemistry, biology.protein, sense organs, Apoptosis Regulatory Proteins |
| الوصف: | Background: A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3’-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. Methods: The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3). Results: The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. Conclusion: The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy. Background Studies in this laboratory have investigated the mechanisms of cell death induced by a new series of anticancer agents that are derivatives of phytochemicals expressed in crucifers. Indole-3-carbinol is a phytochemical found as a conjugate in cruciferous vegetables, and both indole-3-carbinol and one of its major metabolites, 3,3’diindolylmethane (DIM), exhibit a broad range of anticancer and antitumorigenic activities against multiple tumor types [1-6]. Epidemiology studies have correlated consumption of cruciferous vegetables with decreased risk for certain types of cancer [7-11], and indole-3-carbinol and DIM may contribute to cancer chemoprevention associated with these vegetables. The mechanisms of growth inhibition induced by DIM have been wellstudied and include G0/G1 cell cycle arrest, induction of ER stress, induction of apoptosis, activation of aryl hydrocarbon receptor (AhR)-dependent antiestrogenicity, and downregulation of the androgen receptor (AR) [2,5,12-18]. We also synthesized several DIMs substituted in the indole ring and at the methylene carbon bridge to determine structure-activity relationships. A novel series of methylene-substituted DIMs (CDIMs), namely 1,1-bis(3’-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and |
| اللغة: | English |
| تدمد: | 1471-2407 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::238da6d0ce32877ea0e21fb04aa63b83Test http://www.biomedcentral.com/1471-2407/10/669Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....238da6d0ce32877ea0e21fb04aa63b83 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14712407 |
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