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Iwasawa T, Shinomiya T, Ota N, Shibata N, Nakata K, Shiina I, Nagahara Y. Novel Ridaifen-B Structure Analog Induces Apoptosis and Autophagy Depending on Pyrrolidine Side Chain. Biol Pharm Bull 2019; 42:401-410. [PMID: 30828072 DOI: 10.1248/bpb.b18-00643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ridaifen (RID)-B is an analog derived from tamoxifen (TAM). TAM has an antitumor effect by acting as an antagonist to estrogen receptor (ER). However, TAM is known to also induces apoptosis in cancer cells that do not have ER. We clarified that RID-B induces cell death at a lower concentration than TAM, and causes ER-independent apoptosis and autophagy. Based on the results of previous studies, we assumed that RID-B had a unique target different from ER and examined structural activity correlation to determine what kinds of structural features are related to RID-B activity. As a result, we found there was activity even without one of phenyl groups (Ar3) in RID-B and revealed that two pyrrolidine side chains peculiar to RID-B are related to the action. Furthermore, analogs with shorter alkyl side chains induced autophagy, but analogs with certain length of alkyl side chains induced apoptosis. Also, although there is no doubt that RID-B induces apoptosis by causing mitochondrial injury, our results suggested that such injury induced mitochondria-selective autophagy. We revealed that RID-B induce mitophagy and that this mitophagy is a defense mechanism against RID-B. Our results suggest that autophagy was induced against apoptosis caused by mitochondrial dysfunction in RID-B, so the combination of autophagy inhibitor and anticancer-drug can be effective for cancer treatment.
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Affiliation(s)
- Takumi Iwasawa
- Graduate School of Advanced Science and Technology, Tokyo Denki University
| | - Takahisa Shinomiya
- Graduate School of Advanced Science and Technology, Tokyo Denki University
| | - Nozomi Ota
- Faculty of Science, Tokyo University of Science
| | | | - Kenya Nakata
- Graduate School of Science and Engineering, Shimane University
| | | | - Yukitoshi Nagahara
- Graduate School of Advanced Science and Technology, Tokyo Denki University
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2
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Bashash D, Safaroghli-Azar A, Dadashi M, Safa M, Momeny M, Ghaffari SH. Anti-tumor activity of PI3K-δ inhibitor in hematologic malignant cells: Shedding new light on resistance to Idelalisib. Int J Biochem Cell Biol 2017; 85:149-158. [DOI: 10.1016/j.biocel.2017.02.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Revised: 02/05/2017] [Accepted: 02/20/2017] [Indexed: 11/30/2022]
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Al-Howail HA, Hakami HA, Al-Otaibi B, Al-Mazrou A, Daghestani MH, Al-Jammaz I, Al-Khalaf HH, Aboussekhra A. PAC down-regulates estrogen receptor alpha and suppresses epithelial-to-mesenchymal transition in breast cancer cells. BMC Cancer 2016; 16:540. [PMID: 27465411 PMCID: PMC4964287 DOI: 10.1186/s12885-016-2583-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 07/19/2016] [Indexed: 12/31/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features. Methods HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities. Results PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERα+) and estrogen receptor alfa negative (ERα−) breast cancer cells to PAC, which down-regulated ERα in both cell types. This led to complete disappearance of ERα in ERα− cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERα in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERα inhibits PAC-dependent induction of apoptosis, which could be mediated through ERα down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts. Conclusion These results indicate that PAC could be considered as important candidate for future therapeutic options against the devastating TNBC subtype.
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Affiliation(s)
- Huda A Al-Howail
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Hana A Hakami
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.,Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.,Present Address: McGill University Health Center, Montreal, QC, Canada
| | - Basem Al-Otaibi
- Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Amer Al-Mazrou
- Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Maha H Daghestani
- Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia
| | - Ibrahim Al-Jammaz
- Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Huda H Al-Khalaf
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.,The National Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
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4
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Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MGK, Mackey JR, Godbout R, Curtis JM, McMullen TPW, Brindley DN. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 2016; 6:21164. [PMID: 26883574 PMCID: PMC4756695 DOI: 10.1038/srep21164] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 01/14/2016] [Indexed: 02/07/2023] Open
Abstract
Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.
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Affiliation(s)
- Raie T Bekele
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Ganesh Venkatraman
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Rong-Zong Liu
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - Si Mi
- Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada
| | - Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
| | - John R Mackey
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Roseline Godbout
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada
| | - Jonathan M Curtis
- Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada
| | - Todd P W McMullen
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.,Department of Surgery, Walter C Mackenzie Health Science Centre, University of Alberta, Edmonton, T6G 2R7, Alberta, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada
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Abstract
Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER-positive breast cancers. Interestingly, 5–10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome.
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Affiliation(s)
- Subrata Manna
- Department of Biology, Yeshiva University, New York, NY, USA
| | - Marina K Holz
- Department of Biology, Yeshiva University, New York, NY, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA
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6
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Yang L, Yuan X, Wang J, Gu C, Zhang H, Yu J, Liu F. Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro. Oncol Lett 2015; 10:473-478. [PMID: 26171054 DOI: 10.3892/ol.2015.3195] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 04/21/2015] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to investigate the radiosensitizing effects of tamoxifen (TAM), a non-steroidal anti-estrogen drug, in human glioma A172 and U251 cells in vitro. A colony-forming assay revealed that TAM enhances radiosensitivity in A172 and U251 cells. Treatment with TAM also increased the percentage of apoptotic cells subsequent to ionizing radiation, and increased the expression of apoptotic markers, including cleaved caspase-3 and poly(ADP-ribose) polymerase. Ionizing radiation induced G2/M phase arrest, which was alleviated within 24 h when the radiation-induced DNA damage was repaired. However, flow cytometry analysis revealed that TAM treatment delayed the recovery of cell cycle progression. Additional examination demonstrated that TAM-mediated protein kinase C-ι (PKC-ι) inhibition may lead to the activation of pro-apoptotic B-cell lymphoma 2-associated death promoter, and the dephosphorylation of cyclin-dependent kinase 7, resulting in increased cell apoptosis and sustained G2/M phase arrest following exposure to radiation. The present data indicate that the radiosensitizing effects of TAM on glioma cells are partly due to the inhibition of PKC-ι activity in vitro.
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Affiliation(s)
- Lei Yang
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Xiaopeng Yuan
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Jie Wang
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Cheng Gu
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Haowen Zhang
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Jiahua Yu
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
| | - Fenju Liu
- Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, P.R. China
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Hasegawa M, Yasuda Y, Tanaka M, Nakata K, Umeda E, Wang Y, Watanabe C, Uetake S, Kunoh T, Shionyu M, Sasaki R, Shiina I, Mizukami T. A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor. Eur J Med Chem 2013; 71:290-305. [PMID: 24321833 DOI: 10.1016/j.ejmech.2013.11.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 11/02/2013] [Accepted: 11/06/2013] [Indexed: 01/01/2023]
Abstract
In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound 6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure-activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound 25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors.
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Affiliation(s)
- Makoto Hasegawa
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
| | - Yukari Yasuda
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
| | - Makoto Tanaka
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
| | - Kenya Nakata
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Eri Umeda
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Yanwen Wang
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Chihiro Watanabe
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Shoko Uetake
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Tatsuki Kunoh
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
| | - Masafumi Shionyu
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
| | - Ryuzo Sasaki
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
| | - Isamu Shiina
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
| | - Tamio Mizukami
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan
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8
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Ouyang ZX, Li XA. Inhibitory effects of tamoxifen and doxorubicin, alone and in combination, on the proliferation of the MG63 human osteosarcoma cell line. Oncol Lett 2013; 6:970-976. [PMID: 24137447 PMCID: PMC3796417 DOI: 10.3892/ol.2013.1487] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 07/10/2013] [Indexed: 12/02/2022] Open
Abstract
The present study aimed to compare the combined effect of tamoxifen (TAM) and doxorubicin (ADM) with the individual effects of TAM and ADM alone on the MG63 human osteosarcoma cell line. Estrogen receptor (ER) expression was detected in the MG63 cells using reverse transcription PCR. The morphological changes during the inhibition of cell growth were observed using an inverted microscope and a 3-(4, 5-dimethy1-2-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) colorimetric assay following the individual or combined addition of TAM and ADM. ERα and ERβ expression was detected in the MG63 cells. The typical apoptotic cell morphology was observed in all groups, with the exception of the control group. The MTT colorimetric analysis demonstrated that the rate of inhibition of cell proliferation in the combination group was significantly increased compared with that in the other groups (P<0.05). ERα and ERβ expression was detected in the MG63 human osteosarcoma cells. TAM and ADM alone were able to inhibit cell proliferation. The combination of TAM and ADM significantly enhanced the inhibitory effect, partly through the enhanced sensitivity of the cells to ADM by TAM, which caused the inhibition of cell proliferation and apoptosis.
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Affiliation(s)
- Zheng-Xiao Ouyang
- Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
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Tsukuda S, Kusayanagi T, Umeda E, Watanabe C, Tosaki YT, Kamisuki S, Takeuchi T, Takakusagi Y, Shiina I, Sugawara F. Ridaifen B, a tamoxifen derivative, directly binds to Grb10 interacting GYF protein 2. Bioorg Med Chem 2012. [PMID: 23199482 DOI: 10.1016/j.bmc.2012.10.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ridaifen B (RID-B) is a tamoxifen derivative that potently inhibits breast tumor growth. RID-B was reported to show anti-proliferating activity for a variety of estrogen receptor (ER)-positive human cancer cells. Interestingly, RID-B was also reported to possess higher potency than that of tamoxifen even for some ER-negative cells, suggesting an ER-independent mechanism of action. In this study, a T7 phage display screen and subsequent binding analyses have identified Grb10 interacting GYF protein 2 (GIGYF2) as a RID-B-binding protein. Using a cell-based assay, the Akt phosphorylation level mediated by GIGYF2 was found to have decreased in the presence of RID-B.
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Affiliation(s)
- Senko Tsukuda
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
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Sondhi V, Kurkure PA, Vora T, Banavali SD, Vishwanathan S, Medhi S, Kulkarni A, Quereshi S, Arora B. Successful management of multi-focal hepatic infantile hemangioendothelioma using TACE/surgery followed by maintenance metronomic therapy. BMJ Case Rep 2012; 2012:bcr.12.2011.5456. [PMID: 22605610 DOI: 10.1136/bcr.12.2011.5456] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Infantile hepatic hemangioendothelioma (IHE) is a rare angiogenic tumour with diverse clinical presentations and varied course ranging from spontaneous regression to life-threatening complications. The authors report a 2-year boy who presented with respiratory distress and was identified as a case of inoperable multi-focal hepatic IHE. He showed a transient response to trans-arterial-chemo-embolisation and liver resection but had progressive disease despite chemotherapy (prednisolone/vicristine/ifosfamide/cisplatin). Thereafter, he was successfully managed with metronomic therapy using cyclophosphamide and tamoxifen.
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Affiliation(s)
- Vishal Sondhi
- Pediatric Oncology Department, Tata Memorial Hospital, Mumbai, India.
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11
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Li C, Zhou C, Wang S, Feng Y, Lin W, Lin S, Wang Y, Huang H, Liu P, Mu YG, Shen X. Sensitization of glioma cells to tamoxifen-induced apoptosis by Pl3-kinase inhibitor through the GSK-3β/β-catenin signaling pathway. PLoS One 2011; 6:e27053. [PMID: 22046442 PMCID: PMC3203172 DOI: 10.1371/journal.pone.0027053] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 10/10/2011] [Indexed: 11/18/2022] Open
Abstract
Malignant gliomas represent one of the most aggressive types of cancers and their recurrence is closely linked to acquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeutic resistance and enhancing treatment efficacy. Herein, we show by colony formation, Hochest 33342 and TUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhanced significantly the sensitization of a traditional cytotoxic chemotherapeutic agent, tamoxifen-induced apoptosis in C6 glioma cells. Activation of PI3K signaling pathway by IGF-1 protected U251 cells from apoptosis induced by combination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatment showed lower levels of phosphorylated AktSer473 and GSK-3βSer9 than a single treatment of LY294002. Further, we showed a significant decrease of nuclear β-catenin by combination treatment. In response to the inhibition of β-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantly decreased by combination treatment. Our results indicated that the synergistic cytotoxic effect of LY294002 and tamoxifen is achieved by the inhibition of GSK-3β/β-catenin signaling pathway.
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Affiliation(s)
- Cuixian Li
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Chun Zhou
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shaogui Wang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Ying Feng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wei Lin
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Sisi Lin
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Ying Wang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Heqing Huang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peiqing Liu
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yong-Gao Mu
- Department of Neurosurgery/Neuro-oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
- * E-mail: (YGM); (XS)
| | - Xiaoyan Shen
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- * E-mail: (YGM); (XS)
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12
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Akasaka H, Sato F, Morohashi S, Wu Y, Liu Y, Kondo J, Odagiri H, Hakamada K, Kijima H. Anti-apoptotic effect of claudin-1 in tamoxifen-treated human breast cancer MCF-7 cells. BMC Cancer 2010; 10:548. [PMID: 20937153 PMCID: PMC2958956 DOI: 10.1186/1471-2407-10-548] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Accepted: 10/12/2010] [Indexed: 12/31/2022] Open
Abstract
Background Claudin-1 is a membrane protein of tight junctions, and is associated with the development of various cancers. However, the significance of claudin-1 expression in cancer cells is not well understood. Here, we showed for the first time the anti-apoptotic effect of claudin-1 in human breast cancer MCF-7 cells. Methods Human breast cancer MCF-7 and T47 D cells were treated with or without tamoxifen, siRNA against claudin-1, or tamoxifen and claudin-1 siRNA. The samples were analyzed by RT-PCR, Western blotting or immunofluorescent staining. Results The expression of claudin-1 was upregulated in tamoxifen-treated MCF-7 cells, whereas the expression of claudin-1 was not altered in tamoxifen-treated T47 D cells. Knockdown of claudin-1 by siRNA increased the amount of poly (ADP-ribose) polymerase (PARP) regardless of tamoxifen treatment in MCF-7 cells, but not T47 D cells. In the cell membranes of the MCF-7 cells, tamoxifen treatment increased the amount of claudin-1, but decreased the amount of β-catenin. Claudin-1 siRNA increased the amount of E-cadherin in the cytoplasm of the MCF-7 cells as well as the amount of β-catenin in their cell membranes. Conclusion These results indicate that claudin-1 has anti-apoptotic effects, and is involved in the regulation of the expression and subcellular localization of β-catenin and E-cadherin in MCF-7, but not T47 D cells.
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Affiliation(s)
- Harue Akasaka
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Tamoxifen and raloxifene suppress the proliferation of estrogen receptor-negative cells through inhibition of glutamine uptake. Cancer Chemother Pharmacol 2010; 67:285-91. [DOI: 10.1007/s00280-010-1316-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Accepted: 03/28/2010] [Indexed: 10/19/2022]
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14
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Rakıcı S, Gönüllü G, Gürsel SB, Yıldız L, Bayrak IK, Yücel I. Mucinous Cystadenocarcinoma of the Breast with Estrogen Receptor Expression: A Case Report and Review of the Literature. Case Rep Oncol 2009; 2:210-216. [PMID: 20737039 PMCID: PMC2914384 DOI: 10.1159/000253866] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Primary mucinous cystadenocarcinoma (MCA) of the breast was first described by Koenig and Tavassoli in 1998. To our knowledge, only 9 cases of MCA of the breast have been reported. The optimal treatment of MCA could not be defined yet. This article aims to increase the knowledge about this rare variant of breast cancer and to review the literature.
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Affiliation(s)
- Sema Rakıcı
- Department of Radiation Oncology, Atatürk University Faculty of Medicine, Erzurum, Turkey
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15
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Tu SH, Chang CC, Chen CS, Tam KW, Wang YJ, Lee CH, Lin HW, Cheng TC, Huang CS, Chu JS, Shih NY, Chen LC, Leu SJ, Ho YS, Wu CH. Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat 2009; 121:539-53. [PMID: 19655245 DOI: 10.1007/s10549-009-0492-0] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2009] [Accepted: 07/18/2009] [Indexed: 01/22/2023]
Abstract
Enolase-alpha (ENO-1) is a key glycolytic enzyme that has been used as a diagnostic marker to identify human lung cancers. To investigate the role of ENO-1 in breast cancer diagnosis and therapy, the mRNA levels of ENO-1 in 244 tumor and normal paired tissue samples and 20 laser capture-microdissected cell clusters were examined by quantitative real-time PCR analysis. Increased ENO-1 mRNA expression was preferentially detected in estrogen receptor-positive (ER+) tumors (tumor/normal ratio >90-fold) when compared to ER-negative (tumor/normal ratio >20-fold) tumor tissues. The data presented here demonstrate that those patients whose tumors highly expressed ENO-1 had a poor prognosis with greater tumor size (>2 cm, *P = .017), poor nodal status (N > 3, *P = .018), and a shorter disease-free interval (<==1 year, *P < .009). We also found that higher-expressing ENO-1 tumors confer longer distance relapse (tumor/normal ratio = 82.8-92.4-fold) when compared to locoregional relapse (tumor/normal ratio = 43.4-fold) in postsurgical 4-hydroxy-tamoxifen (4-OHT)-treated ER+ patients (*P = .014). These data imply that changes in tumor ENO-1 levels are related to clinical 4-OHT therapeutic outcome. In vitro studies demonstrated that decreasing ENO-1 expression using small interfering RNA (siRNA) significantly augmented 4-OHT (100 nM)-induced cytotoxicity in tamoxifen-resistant (Tam-R) breast cancer cells. These results suggest that downregulation of ENO-1 could be utilized as a novel pharmacological approach for overcoming 4-OHT resistance in breast cancer therapy.
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Affiliation(s)
- Shih-Hsin Tu
- Department of Surgery, Cathay General Hospital, Taipei, Taiwan
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16
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Searovic P, Alonso M, Oses C, Pereira-Flores K, Velarde V, Saez CG. Effect of tamoxifen and retinoic acid on bradykinin induced proliferation in MCF-7 cells. J Cell Biochem 2009; 106:473-81. [DOI: 10.1002/jcb.22031] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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17
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Application of selective estrogen receptor modulators for breast cancer treatment according to their intrinsic nature. Breast Cancer 2008; 15:262-9. [DOI: 10.1007/s12282-008-0063-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2008] [Accepted: 05/09/2008] [Indexed: 01/03/2023]
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18
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Tamoxifen for salivary gland adenoid cystic carcinoma: report of two cases. J Cancer Res Clin Oncol 2008; 134:1151-3. [DOI: 10.1007/s00432-008-0377-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2008] [Accepted: 02/29/2008] [Indexed: 10/22/2022]
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19
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Nagahara Y, Shiina I, Nakata K, Sasaki A, Miyamoto T, Ikekita M. Induction of mitochondria-involved apoptosis in estrogen receptor-negative cells by a novel tamoxifen derivative, ridaifen-B. Cancer Sci 2008; 99:608-14. [PMID: 18167132 PMCID: PMC11159952 DOI: 10.1111/j.1349-7006.2007.00709.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Revised: 11/14/2007] [Accepted: 11/14/2007] [Indexed: 11/29/2022] Open
Abstract
Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor-positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor-negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis-inducing effect of tamoxifen and evaluated the apoptosis-inducing pathway. The estrogen receptor-positive human leukemia cell line HL-60 and estrogen receptor-negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability-detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen-B had more potent cancer cell-damaging activity than tamoxifen. Ridaifen-B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen-B-induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen-B-induced apoptosis was estimated. Ridaifen-B significantly reduced mitochondrial membrane potential, and overexpression of Bcl-2 inhibited ridaifen-B-induced apoptosis. These results suggest that the induction of apoptosis by ridaifen-B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement.
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Affiliation(s)
- Yukitoshi Nagahara
- Department of Biotechnology, College of Science and Engineering, Tokyo Denki University, Hatoyama, Hiki-gun, Saitama, 350-0394, Japan.
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20
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Rulli A, Antognelli C, Prezzi E, Baldracchini F, Piva F, Giovannini E, Talesa V. A possible regulatory role of 17beta-estradiol and tamoxifen on glyoxalase I and glyoxalase II genes expression in MCF7 and BT20 human breast cancer cells. Breast Cancer Res Treat 2006; 96:187-96. [PMID: 16319983 DOI: 10.1007/s10549-005-9078-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The glutathione-dependent glyoxalases system, composed of glyoxalase I (GloI) and glyoxalase II (GloII) enzymes, is involved in the detoxification of methylglyoxal, a by-product of cell metabolism. Aberrations in the expression of glyoxalase genes in several human cancers have been reported. Sometimes, these aberrations seem to differ depending on the organs and on the sensitivity of the tumours to estrogens, as we previously detected in the hormone-responsive breast cancer compared to the hormone-independent bladder cancer. To investigate a possible regulatory role of estrogens, as well as antiestrogens, on glyoxalases system, estrogen receptor (ER)-positive MCF7 and ER-negative BT20 human breast cancer cells were cultured in the presence of 17beta-estradiol (E2) and tamoxifen (TAM) performing two independent experiments. After a 24 h or 4 days treatment, we evaluated GloI and GloII mRNA levels, by Ribonuclease Protection Assay (RPA), enzymatic activities spectrophotometrically and cell proliferation by [3H]thymidine incorporation. We found that both steroid molecules affected glyoxalases gene expression and proliferation in a different manner in the cell lines. The modifications in mRNA levels were accompanied by parallel changes in the enzymatic activities. The possibility that modulation of glyoxalase genes by E2 and TAM are due to the presence of estrogen response elements (ERE) or cross-talk mechanisms by proteins of the estrogen signal transduction pathways are discussed. Knowledge regarding the regulation of glyoxalases by E2 and TAM may provide insights into the importance of this enzymes in human breast carcinomas in vivo.
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Affiliation(s)
- Antonio Rulli
- Department of Surgical Sciences, University of Perugia, Perugia, Italy
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21
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Morán González D, Domínguez-Gil Hurlé A. [Antisense therapy in oncology: present situation]. FARMACIA HOSPITALARIA 2006; 29:269-82. [PMID: 16268744 DOI: 10.1016/s1130-6343(05)73676-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The purpose of antisense therapy is to control the regulation of genes contributing to cancer progression while sparing normal cell growth, which represents a novel alternative with fewer side effects when compared to conventional chemotherapy. Antisense oligonucleotides control cell proliferation by specifically blocking the expression of selected genes, and hence they are being developed as molecular drugs with potential activity for cancer treatment. Extensive clinical information and a number of clinical trials show encouraging results. This review discusses the most significant aspects of this new therapeutic alternative in oncology. Clinical trials performed thus far have demonstrated their short- to mid-term efficacy and safety; however, long-term studies are needed to definitely define their clinical effectiveness and true toxic profile.
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Abstract
The mitochondria have emerged as a novel target for anticancer chemotherapy. This tenet is based on the observations that several conventional and experimental chemotherapeutic agents promote the permeabilization of mitochondrial membranes in cancerous cells to initiate the release of apoptogenic mitochondrial proteins. This ability to engage mitochondrial-mediated apoptosis directly using chemotherapy may be responsible for overcoming aberrant apoptosis regulatory mechanisms commonly encountered in cancerous cells. Interestingly, several putative cancer chemopreventive agents also possess the ability to trigger apoptosis in transformed, premalignant, or malignant cells in vitro via mitochondrial membrane permeabilization. This process may occur through the regulation of Bcl-2 family members, or by the induction of the mitochondrial permeability transition. Thus, by exploiting endogenous mitochondrial-mediated apoptosis-inducing mechanisms, certain chemopreventive agents may be able to block the progression of premalignant cells to malignant cells or the dissemination of malignant cells to distant organ sites as means of modulating carcinogenesis in vivo. This review will examine cancer chemoprevention with respect to apoptosis, carcinogenesis, and the proapoptotic activity of various chemopreventive agents observed in vitro. In doing so, I will construct a paradigm supporting the notion that the mitochondria are a novel target for the chemoprevention of cancer.
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Affiliation(s)
- N Hail
- Department of Clinical Pharmacy, School of Pharmacy, The University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
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23
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Hsu JT, Hung HC, Chen CJ, Hsu WL, Ying C. Effects of the dietary phytoestrogen biochanin A on cell growth in the mammary carcinoma cell line MCF-7. J Nutr Biochem 2005; 10:510-7. [PMID: 15539330 DOI: 10.1016/s0955-2863(99)00037-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/1998] [Accepted: 05/24/1999] [Indexed: 11/21/2022]
Abstract
Studies of the dietary phytoestrogen biochanin A on cell proliferation of the cultured estrogen responsive cells human breast carcinoma MCF-7 showed that biochanin A exhibits biphasic regulation on MCF-7 cells. At concentrations of less than 10 microg/mL, cells respond to biochanin A by increasing cell growth and de novo DNA synthesis. The addition of biochanin A at concentrations of greater than 30 microg/mL significantly inhibited cell growth and DNA synthesis in a dose-dependent fashion, resulting in an IC(50) value of 40 microg/mL. The reversibility of these inhibitory effects by biochanin A appears also to be concentration dependent. Cells previously treated with high concentrations (>60 microg/mL) of biochanin A did not regain normal growth after treatment ceased. Biochanin A was cytostatic at low concentrations (<40 microg/mL) and cytotoxic at higher concentrations. Upon exposure to 100 microg/mL of biochanin A, cell morphology was severely altered, cell volume decreased, and condensation of cell components was clearly noticeable. In addition, biochanin A damaged cell membranes by increasing membrane permeability. These results suggest possible molecular and cellular mechanisms of the action of dietary phytoestrogens on estrogen target cells.
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Affiliation(s)
- J T Hsu
- Department of Animal Sciences, National Taiwan University, Taipei, Taiwan, People's Republic of China
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Kim YJ, Lee CJ, Lee U, Yoo YM. Tamoxifen-induced cell death and expression of neurotrophic factors in cultured C6 glioma cells. J Neurooncol 2005; 71:121-5. [PMID: 15690126 DOI: 10.1007/s11060-004-0984-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The effects of ( Z)-2[ p -(1,2-diphenyl-1-butenyl)phenoxy]-N ,N -dimethylamine citrate (tamoxifen) on cell survival and the expression of neurotrophic factors (NTF) were investigated in rat C6 glioma cells (C6). C6 cells do not express the estrogen receptor. Cytotoxic effect was detected from 24 h after the treatment with 10 microM tamoxifen and increased with time in a dose-dependent manner. C6 cells treated with tamoxifen also displayed various morphological types such as elliptical, round and aggregated form. As the treatment time increased, the proliferation of C6 cells was reduced remarkably and most of them became the round or aggregated form. To examine the relationship of the expression of NTF and the cytotoxicity of tamoxifen, the mRNA level of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and basic fibroblast growth factor (bFGF) was measured after 24 h treatment with tamoxifen by RT-PCR. The expression of mRNA of BDNF or GDNF in C6 cells treated with various concentrations of tamoxifen was comparable to controls. The expression of bFGF mRNA was significantly reduced in C6 cells treated with 10 or 15 microM tamoxifen. The results suggest that tamoxifen exerts cytotoxic effect on estrogen receptor-negative C6 cells through the inhibition of the transcription of bFGF.
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Affiliation(s)
- Yong-Jung Kim
- Department of Biological Sciences, College of Natural Sciences, Inha University, South Korea
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25
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Zheng JG, Tan TZ. Antisense imaging of colon cancer-bearing nude mice with liposome-entrapped 99m-technetium-labeled antisense oligonucleotides of c-myc mRNA. World J Gastroenterol 2004; 10:2563-6. [PMID: 15300907 PMCID: PMC4572164 DOI: 10.3748/wjg.v10.i17.2563] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the feasibility for antisense imaging of the colon cancer with liposome-entrapped 99 m-technetium labeled antisense oligonucleotides as tracers.
METHODS: Fifteen mer single-stranded aminolinked phosphorothioate antisense oligonucleotides of c-myc mRNA were labeled with 99mTc-pertechnetate, then purified and finally entrapped with liposomes to form the labeling compounds, liposome-entrapped 99mTc-labeled antisense oligonucleotides. The LS-174-T cells (colon of adenocarcinoma cell line) were incubated with the labeling compounds to test the uptake rates of LS-174-T cells. Later on, a model of 30 tumor bearing nude mice was constructed by inoculating with 5 × 106 of LS-174-T cells at right flank of each nude mouse. About 10 d later, the model were adminstered by intravenous injection of the liposome-entrapped 99mTc-labeled antisense oligonucleotides. Then some of the tumour bearing nude mice were sacrificed at 0.5, 1, 2, and 4 h after intravenous injection, and proper quantity of liver, spleen, tumor, etc. was obtained. The tissues were counted in a gamma counter, and after correction for decay and background activity, expressed as a percentage of the injected dose. The others whose anterior and posterior whole-body scans were obtained at 1, 1.5, 2, 4, 6 and 24 h with a dual-head bodyscan camera equipped with parallel-hole low-energy collimaters. The ratios of radioactive counts in tumor to that in contralateral equivalent region of abdomen were calculated.
RESULTS: The uptake rates of LS-174-T cells for liposome-entrapped 99mTc-labeled antisense oligonucleotides increased as time prolonged and reach the peak (17.77% ± 2.41%) at 7 h. The biodistributions showed that the rdioactivity in the tumor (13.46% ± 0.20%) of injected dose was the highest at 2 h of intravenous injection of liposome-entrapped 99mTc-labeled antisense oligonucleotides, and then decreased sharply to 4.58% ± 0.45% at 4 h. The tumor was shown clearly in the whole-body scan at 2 h of intravenous injection. The ratios, radioactive counts in tumor to that in contralateral equivalent region of abdomen (1.7332 ± 0.2537), was the highest one at 2 h after intravenous injection of liposome-entrapped 99mTc-labeled antisense oligonucleotides.
CONCLUSION: The liposome-entrapped 99mTc-labeled antisense oligonucleotides deserve being developed into radiopharmaceutics for the colon cancer imaging.
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Abstract
Cancer chemopreventive agents are typically natural products or their synthetic analogs that inhibit the transformation of normal cells to premalignant cells or the progression of premalignant cells to malignant cells. These agents are believed to function by modulating processes associated with xenobiotic biotransformation, with the protection of cellular elements from oxidative damage, or with the promotion of a more differentiated phenotype in target cells. However, an increasing number of chemopreventive agents (e.g., certain retinoids, nonsteroidal anti-inflammatory drugs, polyphenols, and vanilloids) have been shown to stimulate apoptosis in premalignant and malignant cells in vitro or in vivo. Apoptosis is arguably the most potent defense against cancer because it is the mechanism used by metazoans to eliminate deleterious cells. Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of carcinogenesis selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in premalignant cells--in which these pathways are still relatively intact--may be an effective method of cancer prevention. In this review, we construct a paradigm supporting apoptosis as a novel target for cancer chemoprevention by highlighting recent studies of several chemopreventive agents that engage apoptosis pathways.
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Affiliation(s)
- Shi-Yong Sun
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX77030-4095, USA
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Kalra N, Kumar V. c-Fos is a mediator of the c-myc-induced apoptotic signaling in serum-deprived hepatoma cells via the p38 mitogen-activated protein kinase pathway. J Biol Chem 2004; 279:25313-9. [PMID: 15078869 DOI: 10.1074/jbc.m400932200] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The proto-oncogene c-myc encodes a transcription factor that plays a pivotal role in cell proliferation, differentiation, and apoptosis. The signaling mechanism of c-Myc-induced apoptosis was investigated on the human hepatoma Huh7 cells under growth factor-deprived conditions. The apoptotic process did not involve p53. Rather it was dependent on the expression of c-Fos. Activation of caspases 3 and 9 and down-regulation of Bcl2 were observed in the apoptotic process, indicating it to be a mitochondria-dependent event. An increase in the p38 mitogen-activated protein kinase that was mediated by a Rac1-dependent and cdc42-independent pathway eventually leading to up-regulation of c-Fos activity was also observed. Deletion analysis of the promoter region of the c-fos gene indicated that the ATF2-responsive element conferred the Myc-induced expression of c-Fos. Co-expression of the dominant-negative mutants of c-Fos, p38, and Rac1 blocked the Myc-mediated apoptosis. SB20358, a chemical inhibitor of p38 pathway, also specifically blocked the apoptotic signaling by c-Myc. Furthermore, co-expression of the hepatitis B virus X protein (HBx) along with Myc abrogated the apoptotic signals. The HBx expression was associated with an increase in the levels of phosphorylated AKT and down-regulation of c-Fos by Myc. Thus, c-Fos seems be a new mediator of c-Myc-induced apoptosis.
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Affiliation(s)
- Neetu Kalra
- Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
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Tangkeangsirisin W, Hayashi J, Serrero G. PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells. Cancer Res 2004; 64:1737-43. [PMID: 14996734 DOI: 10.1158/0008-5472.can-03-2364] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PC cell-derived growth factor, also known as progranulin, is an M(r) 88,000 growth factor (referred as PCDGF/GP88) overexpressed in human breast cancer. Antisense inhibition of PCDGF/GP88 expression in MDA-MB-468 cells inhibited tumor formation in nude mice. In estrogen receptor-positive cells, PCDGF/GP88 was expressed in response to estradiol and shown to mediate its mitogenic effect. Pathologic studies indicated that PCDGF/GP88 was expressed in 80% of invasive ductal carcinomas in correlation with parameters of poor prognosis. In the present article, the relationship between PCDGF/GP88 expression and tamoxifen resistance was examined in MCF-7 cells. PCDGF/GP88 overexpression rendered MCF-7 cells able to proliferate in the absence of estrogen and in the presence of tamoxifen. The PCDGF/GP88-overexpressing cells formed tumors in ovariectomized nude mice in the absence of estradiol and in its presence, in contrast to MCF-7 cells. Tumor growth of the overexpressing cells was increased significantly when the mice were treated with tamoxifen. PCDGF/GP88 blocked tamoxifen-induced apoptosis by preventing down-regulation of bcl-2 expression and poly(ADP-ribose) polymerase cleavage. In addition, PCDGF/GP88-overexpressing cells presented higher level of the angiogenic factors vascular endothelial growth factor and angiopoietin-1 than MCF-7 control cells. Tamoxifen treatment additionally increased the level of vascular endothelial growth factor. These studies suggest that PCDGF/GP88 plays a critical role in breast cancer tumorigenesis and in the transition to estrogen independence and tamoxifen resistance, a hallmark of poor prognosis. On the basis of the in vivo studies, it is postulated that tamoxifen treatment of patients with estrogen receptor-positive breast tumors overexpressing PCDGF/GP88 could have adverse clinical consequences.
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Tseng SH, Wang CH, Lin SM, Chen CK, Huang HY, Chen Y. Activation of c-Jun N-terminal kinase 1 and caspase 3 in the tamoxifen-induced apoptosis of rat glioma cells. J Cancer Res Clin Oncol 2004; 130:285-93. [PMID: 14997384 DOI: 10.1007/s00432-004-0546-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2003] [Accepted: 01/26/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE The mechanisms of the antitumor effects of tamoxifen upon gliomas are still unclear. In this study, we investigated the role of c-Jun N-terminal kinase-1 (JNK1) and caspase 3 in the tamoxifen-induced apoptosis of rat glioma cells. METHODS Glioma cells were treated with tamoxifen, followed by a cytotoxicity assay to study its effects on the cells, and then a flow-activated cell sorter (FACS) analysis was performed to analyze the cellular apoptosis of the glioma cells. The expression of JNK1 and phospho-specific JNK1 in glioma cells treated with tamoxifen was investigated by Western blot analysis. The activity of caspase 3 in glioma cells was analyzed by caspase activity assay. RESULTS Tamoxifen was demonstrated to exert cytotoxic effects upon and induced apoptosis of the glioma cells in a concentration- and time-dependent manner (P<0.05). Western blot analysis demonstrated that tamoxifen increased the expression of phospho-specific JNK1 in glioma cells, and an increasing concentration of tamoxifen induced an increasing expression of phospho-specific JNK1. Four-hour 50-microM tamoxifen treatment increased the expression of phospho-specific JNK1 to 3.2 times that of the control level in glioma cells. Tamoxifen also increased the activity of caspase 3 in glioma cells. Pretreatment of glioma cells with the antisense oligonucleotide (OGN) of JNK1 immediately prior to tamoxifen treatment suppressed the expression of phospho-specific JNK1 and the activity of caspase 3. The apoptosis fraction of glioma cells induced by 4-h treatment with 50 microM tamoxifen was decreased from 51% to 28% by pretreatment with the antisense OGN of JNK1 (P<0.003), and to 20% by pretreatment with caspase 3 inhibitor (DEVD-CHO) (P<0.0008). CONCLUSIONS The results suggest that the tamoxifen-induced apoptosis of rat glioma cells is related to the activation of the JNK1/caspase 3 signaling pathway; however, the confirmation of the occurrence of such activation in vivo needs further investigation.
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Affiliation(s)
- Sheng-Hong Tseng
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Chung-Shan S. Road, Taipei, Taiwan
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Khalkhali-Ellis Z, Christian AL, Kirschmann DA, Edwards EM, Rezaie-Thompson M, Vasef MA, Gruman LM, Seftor REB, Norwood LE, Hendrix MJC. Regulating the Tumor Suppressor Gene Maspin in Breast Cancer Cells. Clin Cancer Res 2004; 10:449-54. [PMID: 14760064 DOI: 10.1158/1078-0432.ccr-1002-03] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Mammary epithelial cells and the majority of breast cancer tumors require estrogen for continued growth. Antiestrogen therapy alone, or in combination with other drugs, has long been a common procedure for breast cancer treatment and prophylaxis. Thus, there is a critical need to elucidate the mechanism(s) of action of antiestrogen treatment, especially for patients who are at risk of breast cancer development or who are currently receiving hormone therapy. In this study, we examined the ability of hormones to regulate the expression of a tumor suppressor gene, maspin, which is a serine protease inhibitor (serpin) that plays an important role in mammary gland development and is silenced during breast cancer progression. Specifically, our hypothesis tested the clinical efficacy of tamoxifen to regulate maspin expression. EXPERIMENTAL DESIGN We used maspin promoter luciferase reporter plasmids that were transfected into normal human mammary epithelial (HMEC1331) and MCF-7 breast cancer cells, followed by determination of the effect of hormones and their antagonists on maspin promoter activity. At the protein level, cytosolic fractions from both cell types before and after hormone treatment were subjected to Western blot analysis to determine maspin level. RESULTS AND CONCLUSIONS Our studies revealed that the antiestrogen tamoxifen induces maspin promoter activity. Interestingly, antiandrogen flutamide could also induce maspin in both cell lines tested. These observations were further confirmed in patient tissues. These novel findings provide a new mechanism of action for tamoxifen under normal and pathological conditions. More significantly, these findings could have a potential impact on future therapeutic intervention strategies for breast cancer.
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Affiliation(s)
- Zhila Khalkhali-Ellis
- Department of Anatomy and Cell Biology and the Holden Comprehensive Cancer Center at The University of Iowa, Iowa City, Iowa 52242-1109, USA.
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Chen JC, Chang NW, Chung JG, Chen KC. Saikosaponin-A induces apoptotic mechanism in human breast MDA-MB-231 and MCF-7 cancer cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2004; 31:363-77. [PMID: 12943168 DOI: 10.1142/s0192415x03001065] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The effects of Saikosaponin-A on human breast cancer cell lines (MDA-MB-231 and MCF-7) were investigated. Results demonstrated that Saikosaponin-A inhibited the proliferation or viability of the MDA-MB-231 and MCF-7 cells in a dose-dependent manner. Saikosaponin-A treatment of MDA-MB-231 for 3 hours and of MCF-7 cells for 2 hours, respectively caused an obvious increase in the sub-G1 population of cell cycles. Apoptosis in MDA-MB-231 cells was independent of the P53/p21 pathway mechanism and was accompanied by an increased ratio of Bax to Bcl-2 and c-myc levels and activation of caspase-3. In contrast, apoptosis of MCF-7 cells may have been initiated by the Bcl-2 family of proteins and involved p53/p21 dependent pathway mechanism, and was accompanied by an increased level of c-myc protein. Both the apoptosis of MDA-MB-231 cells and MCF-7 cells showed a difference worthy of further research.
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Affiliation(s)
- Jung-Chou Chen
- Department of Chinese Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan.
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Biroccio A, Leonetti C, Zupi G. The future of antisense therapy: combination with anticancer treatments. Oncogene 2003; 22:6579-88. [PMID: 14528283 DOI: 10.1038/sj.onc.1206812] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The current direction in cancer research is rational drug design, which is based on the evidence that transformed cells are characterized by alterations of genes devoted to the regulation of both cell proliferation and apoptosis. A variety of approaches have been carried out to develop new agents selective for cancer cells. Among these, antisense oligonucleotides (ASOs) are one of such class of new agents able to inhibit specifically the synthesis of a particular cancer-associated protein by binding to protein-encoding RNA, thereby preventing RNA function. In the past decade, several ASOs have been developed and tested in preclinical and clinical studies. Many have shown convincing in vitro reduction in target gene expression and promising activity against a wide variety of tumors. However, because of the multigenic alterations of tumors, the use of ASOs as single agents does not seem to be effective in the treatment of malignancies. Antisense therapy that interferes with signaling pathways involved in cell proliferation and apoptosis are particularly promising in combination with conventional anticancer treatment. An overview of the progress of ASOs used in combination therapy is provided.
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Affiliation(s)
- Annamaria Biroccio
- Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy
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Ahn SJ, Yoon MS, Hyuk S, Han W, Yoon YD, Han JS, Noh DY. Phospholipase C-protein kinase C mediated phospholipase D activation pathway is involved in tamoxifen induced apoptosis. J Cell Biochem 2003; 89:520-8. [PMID: 12761885 DOI: 10.1002/jcb.10532] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Tamoxifen (TAM) is the endocrine therapeutic agent the most widely used in the treatment of breast cancer, and it operates primarily through the induction of apoptosis. In this study, we attempted to elucidate the non-ER mediated mechanism behind TAM treatment, involving the phospholipase C-protein kinase C (PLC-PKC) mediated phospholipase D (PLD) activation pathway, using multimodality methods. In TAM treated MCF7 cells, the PLC and PLD protein and mRNA levels increased. Phosphatidylethanol (PEt) and diacylglycerol (DAG) generation also increased, showing increased activity of PLD and PLCgamma1. Translocation of PKCalpha, from cytosol to membrane, was observed in TAM treated cells. By showing that both PKC and PLC inhibitors could reduce the effects of TAM-induced PLD activation, we confirmed the role of PKC and PLC as upstream regulators of PLD. Finally, we demonstrated that TAM treatment reduced the viability of MCF7 cells and brought about rapid cell death. From these results, we confirmed the hypothesis that TAM induces apoptosis in breast cancer cells, and that the signal transduction pathway, involving PLD, PLC, and PKC, constitutes one of the possible mechanisms underlying the non-ER mediated effects associated with TAM.
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Affiliation(s)
- Soo-Jung Ahn
- Cancer Research Institute, College of Medicine, Seoul National University, Seoul 110-744, Korea
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Salami S, Karami-Tehrani F. Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines. Clin Biochem 2003; 36:247-53. [PMID: 12810152 DOI: 10.1016/s0009-9120(03)00007-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Tamoxifen has been reported to show an efficacy in the treatment of breast cancer. Apoptosis could be a major mechanism of its antitumor effect. Therefore, this study has been designed to investigate the biochemical mechanisms of tamoxifen-induced apoptosis in both ER(+) MCF-7 and ER(-) MDA-MB468 breast cancer cell lines. METHODS Trypan blue dye exclusion test, Annexin V-Fluorescein/PI flow cytometry, MTT assay and Hoechst 33258 staining were used to detect cytotoxicity and apoptosis. The activation of caspase-3 was assayed by colorimetric assay kit. Bcl-2 and Bax proteins were estimated by western immunoblotting method. RESULTS Tamoxifen induced apoptosis in both cell lines (chi-square test, p < 0.05). Unlike the MCF-7 cells, which responded to the low concentration (1 microM), the treated MDA-MB468 cells have mainly been affected at a higher dose (20 microM) at which a significant increase was also obtained in the caspase-3 activity (chi-square test, p < 0.05). Interestingly, tamoxifen at doses higher than 2.5 microM increased cell proliferation in the MCF-7 cells. The levels of Bcl-2 and Bax remained unchanged. CONCLUSION Since tamoxifen has induced apoptosis in both cell lines by different mechanisms, it might be concluded that there exists ER(+) and ER(-) pathways for the induction of apoptosis.
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Affiliation(s)
- Siamak Salami
- Clinical Biochemistry Department, School of Medical Science, Tarbiat Modarres University, Tehran, Iran
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35
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Sáez CG, Velásquez L, Montoya M, Eugenín E, Alvarez MG. Increased gap junctional intercellular communication is directly related to the anti-tumor effect of all-trans-retinoic acid plus tamoxifen in a human mammary cancer cell line. J Cell Biochem 2003; 89:450-61. [PMID: 12761879 DOI: 10.1002/jcb.10519] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Additive effects against tumor cells might be achieved by combining anti-neoplastic agents directed against one or more altered mechanisms in cancer. We investigated the participation of gap junctional intercellular communication (GJIC), which is commonly dysfunctional in tumor cells as a possible mediating mechanism of the effect of all-trans-retinoic acid (RA) and tamoxifen (Tx) in MCF-7 human breast cancer cell lines. The combination of RA + Tx stimulated GJIC in approximately 53 +/- 3% of MCF-7 cells as early as after 6 h of treatment remaining communicated through 144 h of culture. The GJIC enhancement occurred along with immunolocalization of Cx26 and 43 at the membrane of contacting cells and correlated with higher protein levels. Cx40 immunoreactive plaques were detected at cell-to-cell contacts during 48 h of RA + Tx treatment that did not involve higher protein expression, to the contrary, a downregulation occurred after 72 h of treatment. Cell proliferation inhibition upon RA + Tx exposure was observed with optimal effects at 96-120 h of culture with an accumulation of cells primarily in G2/M and G0/G1 cell cycle boundaries. An enhancement of the pre-existing E-cadherin levels was observed after drug exposure along with a downregulation of Bcl-2 and C-myc protein levels and a reduction of telomerase activity, suggesting partial tumor phenotype reversion. Blockage of the RA + Tx-induced GJIC with 18-beta-glycyrrhetinic acid (beta-Gly) prevented in 34% the inhibition of MCF-7 proliferation and the E-cadherin increment in 30% at 96 h of culture. GJIC blockage did not alter the downregulation of Bcl-2, c-Myc, or telomerase activity induced by RA + Tx. Our results showed the participation of GJIC as a mediator mechanism of the combined action of RA and Tx in MCF-7 cells. The chemopreventive modulation of GJIC might represent an approachable alternative for the improvement of cancer therapy.
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Affiliation(s)
- Claudia G Sáez
- Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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36
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Callagy G, Cattaneo E, Daigo Y, Happerfield L, Bobrow LG, Pharoah PDP, Caldas C. Molecular classification of breast carcinomas using tissue microarrays. DIAGNOSTIC MOLECULAR PATHOLOGY : THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY, PART B 2003; 12:27-34. [PMID: 12605033 DOI: 10.1097/00019606-200303000-00004] [Citation(s) in RCA: 120] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The histopathologic classification of breast cancer stratifies tumors based on tumor grade, stage, and type. Despite an overall correlation with survival, this classification is poorly predictive and tumors with identical grade and stage can have markedly contrasting outcomes. Recently, breast carcinomas have been classified by their gene expression profiles on frozen material. The validation of such a classification on formalin-fixed paraffin-embedded tumor archives linked to clinical information in a high-throughput fashion would have a major impact on clinical practice. The authors tested the ability of tumor tissue microarrays (TMAs) to sub-classify breast cancers using a TMA containing 107 breast cancers. The pattern of expression of 13 different protein biomarkers was assessed by immunohistochemistry and the multidimensional data was analyzed using an unsupervised two-dimensional clustering algorithm. This revealed distinct tumor clusters which divided into two main groups correlating with tumor grade (P<0.001) and nodal status (P = 0.04). None of the protein biomarkers tested could individually identify these groups. The biological significance of this classification is supported by its similarity with one derived from gene expression microarray analysis. Thus, molecular profiling of breast cancer using a limited number of protein biomarkers in TMAs can sub-classify tumors into clinically and biologically relevant subgroups.
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Affiliation(s)
- Grace Callagy
- Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Researc Centre, United Kingdom
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Simard M, Zhang W, Hinton DR, Chen TC, Weiss MH, Su YZ, Gopalakrishna R, Law RE, Couldwell WT. Tamoxifen-induced growth arrest and apoptosis in pituitary tumor cells in vitro via a protein kinase C-independent pathway. Cancer Lett 2002; 185:131-8. [PMID: 12169386 DOI: 10.1016/s0304-3835(02)00261-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Protein kinase C (PKC), a kinase family involved in cell signal transduction, is overexpressed in most pituitary adenoma cells. We studied the effect of tamoxifen, an estrogen receptor antagonist and also a protein kinase inhibitor, on pituitary tumor cell proliferation and the induction of apoptosis; and we compared its effects with those of another PKC inhibitor, staurosporine. Tamoxifen induced growth arrest and apoptosis in a mouse pituitary adenoma cell line, AtT20, and in low-passage human primary pituitary tumor cell cultures. Staurosporine also inhibited pituitary tumor cell growth. PKC activity in AtT20 cells was inhibited by staurosporine and by prolonged treatment with phorbol myristate acetate, which down-regulates PKC activity, but not by tamoxifen, at the dosages used to induce apoptosis. Our findings suggest that tamoxifen induces apoptosis in AtT20 cells independent of a classical PKC isozyme pathway.
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Affiliation(s)
- Marie Simard
- Department of Neurosurgery, New York Medical College, Valhalla, NY, USA
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38
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Obrero M, Yu DV, Shapiro DJ. Estrogen Receptor-dependent and Estrogen Receptor-independent Pathways for Tamoxifen and 4-Hydroxytamoxifen-induced Programmed Cell Death. J Biol Chem 2002; 277:45695-703. [PMID: 12244117 DOI: 10.1074/jbc.m208092200] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The therapeutic efficacy of tamoxifen (TAM) in cancer therapy is thought to arise primarily from its ability to compete with estrogens for binding to the estrogen receptor (ER). We show that TAM and its active metabolite, 4-hydroxytamoxifen (OHT), can actively induce programmed cell death through distinct ER-dependent and ER-independent pathways. The ER-independent pathway is activated by 10-20 microm TAM and OHT and by 10-20 microm 17beta-estradiol and raloxifene, and occurs in ER-negative cells. The ER dependence of a second pathway, caused by submicromolar concentrations of TAM and OHT, was demonstrated by the ability of the ER ligands 17beta-estradiol, raloxifene, and ICI 182,780 to effectively block the cell death-inducing effects of TAM and OHT. Because the p38-specific inhibitor SB203580 blocks OHT.ER-induced cell death, stress kinase pathways are likely involved. ER-independent cell death triggers classic caspase-dependent apoptosis. However, although OHT.ER triggers some hallmarks of apoptosis, including Bax translocation and cytochrome c release, the absence of poly(ADP-ribose) polymerase cleavage or DNA laddering indicates that the death pathway involved is caspase-independent. The OHT.ER-dependent cell death pathway appears to diverge from classical apoptosis at the level of caspase 9 activation. The ability to promote ER-dependent programmed cell death represents a novel activity of TAM and OHT.
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Affiliation(s)
- Maria Obrero
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
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39
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Formby B, Wiley T. Inhibition of Cell Growth and Induction of Apoptosis. Breast Cancer 2002. [DOI: 10.1201/b14039-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Strohmeier R, Roller M, Sänger N, Knecht R, Kuhl H. Modulation of tamoxifen-induced apoptosis by peripheral benzodiazepine receptor ligands in breast cancer cells. Biochem Pharmacol 2002; 64:99-107. [PMID: 12106610 DOI: 10.1016/s0006-2952(02)01059-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The peripheral benzodiazepine receptor (PBR), an integral protein of the mitochondrial membrane, is involved in the formation of mitochondrial permeability transition (MPT) pores. The opening of the MPT-leading to the dissipation of the inner-mitochondrial transmembrane potential (deltapsi(m))-is considered to be an early apoptotic event. Therefore, we investigated the effect of the high-affinity PBR ligands Ro5-4684 and PK 11195 on tamoxifen (TAM)-induced apoptosis in MCF-7 and BT-20 breast cancer cell lines. Application of 100 nM TAM led to induction of apoptosis in both cell lines. Estrogene receptor (ER)-positive MCF-7 cells arrested in G(2/M) by TAM treatment showed no general dissipation of deltapsi(m), but reduction of deltapsi(m) was observed in a population of cells with high deltapsi(m). In ER-negative BT-20 cells TAM treatment induced no arrest of the cell cycle but dissipation of deltapsi(m). In both cell lines, nanomolar concentrations of the PBR ligands, which showed minor pro-apoptotic action themselves, reduced TAM-induced decrease of deltapsi(m) and apoptosis. In MCF-7 cells, a reduction of bcl-2 protein expression by TAM treatment was abolished by a combination of TAM with PBR ligands. Bax protein expression in BT-20 cells showed a significant increase in TAM-treated cells after 24hr but was not increased when treated with TAM and PBR ligands. From these findings, we concluded that binding of PBR ligands in nanomolar concentrations protects cells against apoptosis.
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Affiliation(s)
- Renate Strohmeier
- Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Universitätsfrauenklinik, Theordor-Stern Kai 7, Frankfurt, Germany
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Abstract
Selective oestrogen receptor modulators (SERMs) are compounds that interact with the oestrogen receptor and have tissue-specific effects distinct from those of oestradiol, acting as an oestrogen agonist in some tissues and as an antagonist in others. The development of SERMs that selectively interact with specific receptors, coactivators and corepressors in different organ systems offers the possibility of improving the risk:benefit profile relative to hormone replacement therapy. Tamoxifen is a SERM that acts as an oestrogen antagonist in breast tissue and is currently being used for the treatment and prevention of breast cancer. Tamoxifen also exhibits oestrogen-agonistic properties in the endometrium and increases the risk of endometrial cancer. Oestrogen and another SERM, raloxifene, have been shown to prevent osteoporosis. The effects of oestrogens on cognitive functions are currently being investigated. Recent data reveal the lack of secondary prevention of coronary heart disease with oestrogen. Oestrogen has been used to treat menopausal symptoms, whereas the SERMs have been shown to induce hot flushes. Current research is focused on producing the ideal SERM, which would have benefits over existing SERMs in terms of preventing cancer, cardiovascular disease, osteoporosis and menopausal symptoms, improving cognitive functions, and have a significantly better toxicity profile in terms of endometrial cancer and thromboembolic events.
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Affiliation(s)
- Banu Arun
- Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
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Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC. Estradiol up-regulates antiapoptotic Bcl-2 messenger ribonucleic acid and protein in tumorigenic ovarian surface epithelium cells. Endocrinology 2001; 142:2351-60. [PMID: 11356682 DOI: 10.1210/endo.142.6.8144] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Most epithelial ovarian tumors appear to arise from the ovarian surface epithelium (OSE). Even though it has been suggested that estrogen may be associated with ovarian tumorigenesis, the exact role of estrogen in the regulation of apoptosis in neoplastic OSE cells remains uncertain. Immortalized OSE (IOSE) cell lines were generated from human normal OSE. These cell lines represent early neoplastic (IOSE-29), tumorigenic (IOSE-29EC), and late neoplastic (IOSE-29EC/T4 and IOSE-29EC/T5) transformation stages from human normal OSE. The present studies demonstrated that both mRNAs and proteins of estrogen receptor (ER) alpha and beta were expressed in IOSE cell lines. No difference was observed in normal OSE and IOSE-29 cells, whereas treatment with 17beta-estradiol (E(2); 10(-8)-10(-6) M) resulted in an increased thymidine incorporation and DNA content per culture in IOSE-29EC cells. This effect of E(2) was attenuated with tamoxifen treatment (10(-6) M), the estrogen antagonist, suggesting that the effect of E(2) is mediated through specific ERs. There was no stimulatory effect on thymidine incorporation before day 6, but after 6 days of E(2) treatment, thymidine incorporation was significantly increased. Because the ratio of thymidine incorporation to DNA content per culture did not change, this E(2) effect does not appear to indicate stimulation of proliferation but, rather, inhibition of apoptosis. In addition, treatment with tamoxifen (10(-6) M) induced apoptosis up to 3-fold in IOSE-29EC cells, whereas cotreatment with E(2) (10(-8)-10(-6) M) plus tamoxifen attenuated tamoxifen-induced apoptosis in a dose-dependent manner. Both proapoptotic bax and antiapoptotic bcl-2 at messenger RNA (mRNA) and protein levels were expressed in IOSE cell lines. Interestingly, treatments with E(2) resulted in a significant increase of bcl-2 mRNA and protein levels (2- and 1.7-fold, respectively), whereas no difference was observed in bax mRNA level. Thus, E(2) may enhance survival of IOSE-29EC by up-regulating bcl-2, and antiapoptotic bcl-2 may be a dominant regulator of apoptotic pathway in these cells. In conclusion, the present study indicates that early neoplastic (IOSE-29), tumorigenic (IOSE-29EC), and late neoplastic (IOSE-29EC/T4 and T5) OSE cells expressed both ERalpha and ERbeta at the mRNA and protein levels. In addition, E(2) prevented tamoxifen induced-apoptosis through ERs. The mechanism of E(2) action may be associated with up-regulation of bcl-2 gene at mRNA and protein levels. These results suggest that estrogen may play a role in ovarian tumorigenesis by preventing apoptosis in tumorigenic OSE cells.
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Affiliation(s)
- K C Choi
- Department of Obstetrics and Gynaecology, British Columbia Women's Hospital, University of British Columbia, Vancouver, Canada
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Lee YS, Kang YS, Lee SH, Kim JA. Role of NAD(P)H oxidase in the tamoxifen-induced generation of reactive oxygen species and apoptosis in HepG2 human hepatoblastoma cells. Cell Death Differ 2000; 7:925-32. [PMID: 11279538 DOI: 10.1038/sj.cdd.4400717] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Previously, tamoxifen (TAM) has been shown to induce apoptosis through elevation of intracellular Ca2+ in HepG2 human hepatoblastoma cells. In this study we investigated the role of reactive oxygen species (ROS) in the TAM-induced apoptosis, and interrelationship between intracellular Ca2+ and ROS. TAM induced a slow and sustained increase in intracellular ROS level. An antioxidant, N-acetylcysteine significantly inhibited both ROS production and apoptosis induced by TAM, suggesting that ROS may play an essential role in the TAM-induced apoptosis. In a time frame ROS generation followed intracellular Ca2+ increase, and the extracellular and intracellular Ca2+ chelation with EGTA and BAPTA/AM, respectively, completely inhibited the TAM-induced ROS production, indicating that intracellular Ca2+ may mediate the ROS generation. Inhibitors of NAD(P)H oxidase, diphenylene iodonium, phenylarsine oxide and neopterine, significantly blocked the TAM-induced ROS generation and apoptosis, implying that this oxidase may act as a source enzyme for the production of ROS. These results suggest that non-phagocytic NAD(P)H oxidase may play a novel role as a mediator of the apoptosis associated with intracellular Ca2+ in HepG2 cells.
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Affiliation(s)
- Y S Lee
- Department of Physiology, College of Medicine, Kwandong University, Kangnung 210-701, Korea
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Wu WM, Suen JL, Lin BF, Chiang BL. Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL-lpr/lpr mice. Immunology 2000; 100:110-8. [PMID: 10809966 PMCID: PMC2326982 DOI: 10.1046/j.1365-2567.2000.00998.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Previous study suggested that MRL-lpr/lpr mice treated with tamoxifen (TAM) had less severe proteinuria, reduced serum titre of anti-dsDNA autoantibodies and an increased survival rate. To investigate further the regulatory mechanisms of TAM on MRL-lpr/lpr female mice, a total dose of 200 microg per mice (5.5 mg/kg) was given every 2 weeks subcutaneously, while the control mice were injected with oil only. After being treated with TAM four times, the mice were killed and cellular functions were evaluated. The TAM-treated groups had smaller sized spleen and lymph nodes. Flow cytometric analysis of splenocytes had a significantly lower percentage of cell number of T cells and double negative T cells (CD4- CD8- T cells). There was no difference in cytokine production (interleukin (IL)-2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma)) from splenocytes stimulated with concanavalin A (Con A) or cytokines (IL-6) secreted by peritoneal exudate cells when stimulated with lipopolysaccharide (LPS). However, IL-2 from lymph node cells was significantly higher on TAM-treated mice. Finally, splenocytes or purified T cells stimulated with anti-CD3 antibody plus cross-linking immunoglobulin G (IgG) of the TAM-treated group had higher 3H-incorporation of proliferation assay compared with that of control groups. In vitro study further demonstrated that IL-2-activated proliferation of lymph node double negative (DN) T cells can be inhibited by TAM treatment in a dose-dependent manner. Our finding demonstrated that TAM may potentially influence T cells and modulate the immune function, which offers a novel approach to explore the feasibility of hormone therapy for autoimmune diseases.
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Affiliation(s)
- W M Wu
- Graduate Institute of Microbiology, College of Agriculture, and Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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45
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Walter AW, Gajjar A, Reardon DA, Thompson SJ, Langston JW, Jones-Wallace D, Kun LE, Heideman RL. Tamoxifen and carboplatin for children with low-grade gliomas: a pilot study at St. Jude Children's Research Hospital. J Pediatr Hematol Oncol 2000; 22:247-51. [PMID: 10864056 DOI: 10.1097/00043426-200005000-00010] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE The authors conducted a single-arm, prospective study using tamoxifen and carboplatin for the treatment of children with progressive or symptomatic low-grade gliomas. PATIENTS AND METHODS Fourteen children with consecutively diagnosed cases of low-grade glioma were enrolled in this Study; all patients were younger than 14 years. One patient was excluded after induction chemotherapy because of the diagnosis of a nonmalignant condition. Patients were treated with daily tamoxifen (20 mg/m2 administered twice per day) in addition to targeted, monthly intravenous carboplatin at an area under the curve (AUC) exposure of 6.5 mg/mL x minute for 1 year or until they had clinical or radiologic evidence of disease progression. RESULTS The median age at diagnosis was 5.3 years, the median age at initiation of chemotherapy was 8.3 years. Eight patients had tumors of the hypothalamus/optic pathway, two patients had thalamic tumors, and one patient each had tumors in the temporal lobe, tectum, and brain stem. Tumor histologic findings included fibrillary astrocytoma (n = 2), juvenile pilocytic astrocytoma (n = 6), and oligodendroglioma (n = 1). The best response to therapy was a partial response in two patients, stable disease in nine patients, and progressive disease in two patients. The overall survival at 3 years is 69%. The 3-year progression-free survival is 47%. Tamoxifen and carboplatin chemotherapy did not result in a significant number of objective responses in children with low-grade gliomas. The progression-free survival is similar to that of other published series. Nonmyelosuppressive agents such as tamoxifen deserve additional evaluation in the treatment of children with low-grade gliomas.
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Affiliation(s)
- A W Walter
- Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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46
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Hoff PM, Valero V, Buzdar AU, Singletary SE, Theriault RL, Booser D, Asmar L, Frye D, McNeese MD, Hortobagyi GN. Combined modality treatment of locally advanced breast carcinoma in elderly patients or patients with severe comorbid conditions using tamoxifen as the primary therapy. Cancer 2000; 88:2054-60. [PMID: 10813717 DOI: 10.1002/(sici)1097-0142(20000501)88:9<2054::aid-cncr11>3.0.co;2-j] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND The purpose of the current study was to evaluate the objective response rate and possibility of breast-conserving surgery using neoadjuvant tamoxifen in the multimodality treatment, including surgery and radiotherapy, of elderly or frail patients with locally advanced breast carcinoma. METHODS Forty-seven patients age > 75 years or age < 75 years with comorbid conditions and locally advanced breast carcinoma were treated with neoadjuvant tamoxifen (20 mg/day) for 3-6 months. This was followed by surgery and radiotherapy when feasible and adjuvant tamoxifen for 5 years or until disease recurrence. RESULTS The median age of the patients was 72 years (range, 48-86 years). Approximately 22% had T3 lesions, 57% had T4 lesions, 22% were Stage II (AJCC Manual for Staging Cancer, 3rd edition), and 78% were Stage III. Eighty percent were estrogen receptor positive. After 6 months of treatment with neoadjuvant tamoxifen, a response rate of 47% was observed, including a complete response rate of 6%. Twenty-nine patients (62%) were rendered free of disease by surgery, including 5 with breast-conserving procedures. After a median follow-up of 40 months, 23 patients (49%) remained disease free. The median survival time had not been reached at the time of last follow-up. No major toxicity was observed, with the exception of one patient who developed a possible tamoxifen-related Stage I endometrial carcinoma. The estimated 2-year and 5-year progression free and overall survival rates were 50% and 41%, and 83% and 59%, respectively. CONCLUSIONS The results of the current study show that neoadjuvant tamoxifen was effective in the treatment of elderly or frail patients with locally advanced breast carcinoma with estrogen receptor positive tumors, and resulted in a reasonable response rate, including complete responses and good overall survival.
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Affiliation(s)
- P M Hoff
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA
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Hawkin RA, Arends MJ, Ritchie AA, Langdon S, Miller WR. Tamoxifen increases apoptosis but does not influence markers of proliferation in an MCF-7 xenograft model of breast cancer. Breast 2000; 9:96-106. [PMID: 14731708 DOI: 10.1054/brst.2000.0140] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Twenty-four nude mice bearing MCF-7 breast cancer cells grown as xenografts and treated with tamoxifen (2.5 mg slow-release pellet) were studied for up to 35 days. Tumour size was measured in 2 dimensions at regular time-intervals and tumours were harvested on each of days 2, 4, 7, 14, 28 and 35 after the start of treatment. Control animals (8) received no treatment and the tumours were harvested after 0 or 35 days. Tumour sections were assessed for prevalence of apoptosis and mitosis and examined immunocytochemically for Ki(67)(MIB-1) and bcl-2 expression. Tumours increased in size during tamoxifen-treatment, but at a significantly slower rate (max. 2.6-fold) than in the untreated control animals; thus tumours not actually regressing may, nevertheless, be responding significantly to tamoxifen. MIB-1 and bcl-2 immunostaining and mitosis failed to show any consistent change over the period of study. Apoptosis, however, increased progressively and significantly to day-28 in tamoxifen-treated tumours, reaching approximately a 5-fold increase over day-0 values, then decreasing again to nearly 3-fold by day-35 (P= 0.0002). The apoptosis: mitosis ratio in treated tumours also increased to approximately 10-fold on day-28 over day-0 values, decreasing to nearly 4-fold by day-35 (P= 0.037). Within the treated group, apoptosis was significantly inversely correlated with both mitosis (R = -0.38, P= 0.03) and expression of bcl-2 (R = -0.48, P= 0.0056) and strongly positively correlated with both time on tamoxifen (R = +0.63, P= 0.0003) and the % inhibition of growth by tamoxifen (R = +0.58,P = 0.0012) in the 28 individual, treated tumours (estimated relative to the mean growth rate in the controls). The apoptosis: mitosis ratio was also inversely correlated with bcl-2 expression (R = -0.56, P= 0.0021) and positively correlated with both time on tamoxifen (R = +0.50, P= 0.0068) and % inhibition of growth (R = +0.56, P= 0.0019). In this hormone-sensitive tumour model for breast cancer, in which tamoxifen caused inhibition rather than regression, it was not possible to detect significant changes in the marker proteins Ki(67)and bcl-2, or in the prevalence of mitosis in relation to treatment; these factors may therefore not be accurate indices of response to tamoxifen in all situations. By contrast, however, tamoxifen induced a significant, early increase in the prevalence of apoptosis associated with inhibition of tumour growth and an inverse relationship in both mitosis and bcl-2 expression, suggesting that apoptosis may be an accurate and sensitive early marker of even a moderate response to tamoxifen.
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Affiliation(s)
- R A Hawkin
- Edinburgh Breast Unit Research Group, The Medical School, Teviot Place, Edinburgh EH8 9AG, UK
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48
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Higa GM. New generation aromatase inhibitors in breast cancer. Weighing out potential costs and benefits. PHARMACOECONOMICS 2000; 17:121-132. [PMID: 10947336 DOI: 10.2165/00019053-200017020-00002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Endocrine therapy is the oldest and still one of the most effective forms of systemic therapy for breast cancer. Unfortunately, only one-third of all breast carcinomas respond to a strategy that modifies the activity of estrogen at the level of the tumour. Therefore, it is important that patients with cancer likely to respond are reliably identified. Substantial evidence indicates that tumour estrogen receptor level is the best predictor of response to hormonal therapy. Although antiestrogen therapy is still considered the endocrine modality of choice for all stages of breast cancer, there is renewed interest in finding new agents with improved therapeutic indices. The development of agents which selectively suppress aromatase, a key enzyme in estrogen biosynthesis, can be attributed not only to the importance of extraglandular aromatase activity, but also to the unparalleled success of tamoxifen. The present status, emerging roles and concerns of the new aromatase inhibitors are discussed in order to assess their potential costs and therapeutic merit.
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Affiliation(s)
- G M Higa
- School of Pharmacy, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA.
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Kim JA, Kang YS, Jung MW, Lee SH, Lee YS. Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells. Cancer Lett 1999; 147:115-23. [PMID: 10660097 DOI: 10.1016/s0304-3835(99)00284-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca2+. This effect was completely inhibited by the extracellular Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly inhibited by flufenamic acid (FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.
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Affiliation(s)
- J A Kim
- Physiology Section, College of Pharmacy, Yeungnam University, Kyongsan, South Korea
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Pan G, Vickers SM, Pickens A, Phillips JO, Ying W, Thompson JA, Siegal GP, McDonald JM. Apoptosis and tumorigenesis in human cholangiocarcinoma cells. Involvement of Fas/APO-1 (CD95) and calmodulin. THE AMERICAN JOURNAL OF PATHOLOGY 1999; 155:193-203. [PMID: 10393851 PMCID: PMC1866679 DOI: 10.1016/s0002-9440(10)65113-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/23/1999] [Indexed: 01/06/2023]
Abstract
We have previously demonstrated that tamoxifen inhibits the growth of human cholangiocarcinoma cells in culture and inhibits tumor growth when cells are injected into nude mice. However, the mechanism of action of tamoxifen remains unknown. Here we demonstrate that tamoxifen and trifluoperazine, both potent calmodulin antagonists, induce apoptosis in vitro, probably acting via the Fas system, in human cholangiocarcinoma cells. Human cholangiocarcinoma cell lines heterogeneously express Fas antigen on their surface. Fas-negative and Fas-positive surface-expressing cells were isolated, cloned, and cultured. Fas antibody, tamoxifen, and trifluoperazine induced dose-dependent apoptosis only in Fas-positive cells; Fas-negative cells were unaffected. Furthermore, apoptosis induced by tamoxifen in Fas-positive cells was blocked by an inhibitory Fas antibody. Tamoxifen was not acting through an anti-estrogenic mechanism, because neither Fas-negative nor Fas-positive cells expressed estrogen receptors and the pure anti-estrogen compound, ICI 182780, did not induce apoptosis in either cell line. Fas-negative cells, but not Fas-positive cells, were able to produce tumors when subcutaneously injected into nude mice. These findings suggest Fas may be a candidate oncogene involved in the pathogenesis of cholangiocarcinoma. Furthermore, the similarity between the pro-apoptotic effects of tamoxifen and trifluoperazine support an underlying molecular mechanism for Fas-mediated apoptosis that involves calmodulin.
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Affiliation(s)
- G Pan
- Departments of Pathology,* Surgery,dagger and Medicine,double dagger University of Alabama at Birmingham, USA
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