The Experts below are selected from a list of 12891 Experts worldwide ranked by ideXlab platform
Jere D. Haas - One of the best experts on this subject based on the ideXlab platform.
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impact of Iron Depletion without anemia on performance in trained endurance athletes at the beginning of a training season a study of female collegiate rowers
International Journal of Sport Nutrition and Exercise Metabolism, 2011Co-Authors: Diane M. Dellavalle, Jere D. HaasAbstract:The objective of this study was to determine the impact of Iron Depletion without anemia on performance in a sample of female collegiate rowers at the beginning of a training season (August 2008, January 2009, and September 2009). One hundred sixty-five female collegiate rowers from 5 colleges and universities in central New York State participated in a screening of Iron status. Blood hemoglobin (Hgb), serum ferritin (sFer), and soluble transferrin receptor were measured to determine prevalence of Iron Depletion and anemia. Rowers' habitual moderate and vigorous physical activity, as well as their best time to complete a 2-km simulated race during the previous 3 months, were self-reported. Sixteen rowers (10%) were identified as anemic (Hgb <12.0 g/dl). Using a sFer cutoff of <20.0 μg/L, 30% (n = 44) of the nonanemic rowers were identified as Iron depleted without anemia and reported 2-km times ~21 s slower (p < .004) than rowers with normal Iron status. Given the high prevalence of Iron Depletion reported in this and other studies, screening for low Iron stores at the start of a training program in female athletes involved in an endurance sport may be clinically useful. In this study, Iron-depleted rowers (sFer <20-25 μg/L) reported a decrease in performance time compared with those with normal Iron stores.
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Impact of Iron Depletion Without Anemia on Performance in Trained Endurance Athletes at the Beginning of a Training Season: A Study of Female Collegiate Rowers
International journal of sport nutrition and exercise metabolism, 2011Co-Authors: Diane M. Dellavalle, Jere D. HaasAbstract:The objective of this study was to determine the impact of Iron Depletion without anemia on performance in a sample of female collegiate rowers at the beginning of a training season (August 2008, January 2009, and September 2009). One hundred sixty-five female collegiate rowers from 5 colleges and universities in central New York State participated in a screening of Iron status. Blood hemoglobin (Hgb), serum ferritin (sFer), and soluble transferrin receptor were measured to determine prevalence of Iron Depletion and anemia. Rowers' habitual moderate and vigorous physical activity, as well as their best time to complete a 2-km simulated race during the previous 3 months, were self-reported. Sixteen rowers (10%) were identified as anemic (Hgb
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Iron Depletion without anemia and physical performance in young women.
The American journal of clinical nutrition, 1997Co-Authors: Y I Zhu, Jere D. HaasAbstract:Studies in laboratory animals found that Iron deficiency without anemia decreased oxidative capacity and increased reliance on carbohydrate as the substrate for energy, thereby causing impaired endurance. The purpose of this cross-sectional study was to investigate the relation between Iron deficiency without anemia and physical performance in healthy active women aged 19-36 y. Iron-status assessment included determination of hemoglobin, hematocrit, transferrin saturation, and serum ferritin values. Dietary Iron intake was assessed by frequency questionnaires and physical activity level was estimated by frequency questionnaires and 2-wk records. Fifteen women with normal Iron status and 15 women with Iron Depletion (serum ferritin < 12 micrograms/L) were chosen randomly from a group of 69 nonanemic women and given physical-performance tests, including determinations of maximum oxygen consumption (VO2max), ventilatory threshold, and delta-efficiency. There were no significant differences between the two groups in body size, body composition, physical activity level, dietary Iron intake, delta-efficiency, or ventilatory threshold. Compared with the Iron-depleted group, the Iron-sufficient group had significantly higher hemoglobin, transferrin saturation, and serum ferritin values and a significantly greater tendency to use Iron supplements. When physical activity level and fat-free mass were controlled for, the Iron-depleted group had a significantly lower VO2max. The difference in VO2max was significantly associated with serum ferritin concentration; hemoglobin value was not a significant confounder. Therefore, reduction of VO2max in nonanemic women with Iron Depletion was likely caused by factors related to reduced body Iron storage but was unrelated to decreased oxygen-transport capacity of the blood.
Jonathan J Powell - One of the best experts on this subject based on the ideXlab platform.
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dietary Iron Depletion at weaning imprints low microbiome diversity and this is not recovered with oral nano fe iii
MicrobiologyOpen, 2015Co-Authors: Dora I A Pereira, Mohamad F Aslam, David M Frazer, Annemarie Schmidt, Gemma E Walton, Anne L Mccartney, Glenn R Gibson, G J Anderson, Jonathan J PowellAbstract:Alterations in the gut microbiota have been recently linked to oral Iron. We conducted two feeding studies including an initial diet-induced Iron-Depletion period followed by supplementation with nanoparticulate tartrate-modified ferrihydrite (Nano Fe(III): considered bioavailable to host but not bacteria) or soluble ferrous sulfate (FeSO4: considered bioavailable to both host and bacteria). We applied denaturing gradient gel electrophoresis and fluorescence in situ hybridization for study-1 and 454-pyrosequencing of fecal 16S rRNA in study-2. In study-1, the within-community microbial diversity increased with FeSO4 (P = 0.0009) but not with Nano Fe(III) supplementation. This was confirmed in study-2, where we also showed that Iron Depletion at weaning imprinted significantly lower within- and between-community microbial diversity compared to mice weaned onto the Iron-sufficient reference diet (P < 0.0001). Subsequent supplementation with FeSO4 partially restored the within-community diversity (P = 0.006 in relation to the continuously Iron-depleted group) but not the between-community diversity, whereas Nano Fe(III) had no effect. We conclude that (1) dietary Iron Depletion at weaning imprints low diversity in the microbiota that is not, subsequently, easily recovered; (2) in the absence of gastrointestinal disease Iron supplementation does not negatively impact the microbiota; and (3) Nano Fe(III) is less available to the gut microbiota.
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Dietary Iron Depletion at weaning imprints low microbiome diversity and this is not recovered with oral Nano Fe(III).
MicrobiologyOpen, 2014Co-Authors: Dora I A Pereira, Mohamad F Aslam, David M Frazer, Annemarie Schmidt, Gemma E Walton, Anne L Mccartney, Glenn R Gibson, G J Anderson, Jonathan J PowellAbstract:Alterations in the gut microbiota have been recently linked to oral Iron. We conducted two feeding studies including an initial diet-induced Iron-Depletion period followed by supplementation with nanoparticulate tartrate-modified ferrihydrite (Nano Fe(III): considered bioavailable to host but not bacteria) or soluble ferrous sulfate (FeSO4: considered bioavailable to both host and bacteria). We applied denaturing gradient gel electrophoresis and fluorescence in situ hybridization for study-1 and 454-pyrosequencing of fecal 16S rRNA in study-2. In study-1, the within-community microbial diversity increased with FeSO4 (P = 0.0009) but not with Nano Fe(III) supplementation. This was confirmed in study-2, where we also showed that Iron Depletion at weaning imprinted significantly lower within- and between-community microbial diversity compared to mice weaned onto the Iron-sufficient reference diet (P
Toshiaki Ohara - One of the best experts on this subject based on the ideXlab platform.
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Iron Depletion is a novel therapeutic strategy to target cancer stem cells.
Oncotarget, 2017Co-Authors: Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Yasuko Tomono, Hiroshi Tazawa, Yuki Katsura, Hajime Kashima, Takuya Kato, Shunsuke KagawaAbstract:Adequate Iron levels are essential for human health. However, Iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of Iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, Iron Depletion by the Iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, Iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and Iron Depletion may be a novel therapeutic strategy to target CSCs.
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Iron Depletion induced downregulation of n cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer
International Journal of Oncology, 2016Co-Authors: Seishi Nishitani, Toshiaki Ohara, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Yasuhiro Shirakawa, Shinichiro Watanabe, Toshiyoshi FujiwaraAbstract:Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, Iron Depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased Iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased Iron conditions were made using an Iron-Depletion diet in mice and the Iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased Iron conditions. In vitro study showed that decreased Iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased Iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.
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Iron Depletion enhances the effect of sorafenib in hepatocarcinoma
Cancer biology & therapy, 2016Co-Authors: Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki KimuraAbstract:ABSTACT Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that Iron Depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed Iron Depletion therapy including Iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of Iron Depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum Iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total Iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low Iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar®) and/or deferasirox (EXJADE®) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both Iron Depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by Iron Depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.
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Abstract 5608: Iron Depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma.
Experimental and Molecular Therapeutics, 2013Co-Authors: Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Yasuhiro Shirakawa, Shinichiro Watanabe, Masafumi Kataoka, Nouso Kazuhiro, Toshiyoshi FujiwaraAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Purpose. Sorafenib is a multiple kinase inhibitor approved for advanced hepatocellular carcinoma(HCC). However, we couldn't get sufficient effect in clinical use compared to other cancers. Iron metabolism and relationship with cancer cells have been studied for a long time. Iron overload is known to associate with an increased risk of HCC, and the recent study suggests that Iron Depletion can induce anti-cancer effect against HCC. We hypothesized that Iron Depletion enhance the effect of sorafenib and investigated it. Experimental Design. HepG2 (Human hepatocellular liver carcinoma cell line) was used in this study. We used sorafenib and an oral Iron chilator, deferasirox (EXJADE TM). The effects of each agent and combination of both were examined by using cell viability assay. We examined anti-proliferative mechanism in vitro using Flow Cytometry and Western blot analysis. Results. We examined the cell viability of HepG2. Each treatment by sorafenib and deferasirox suppressed the cancer cell proliferation on dose dependent manner. The IC50 values of 48hours of sorafenib was 1.45μM/L,and that of deferasirox was 1.37μM/L. We examined the possibility of combination therapy. The each cell viability of sorafenib 1μM and deferasirox 10μM was 59.4% and 28.1%, the combination one was 21.8%. The combination index was 0.616 in that status, which suggested synergistic effect. To evaluate anti-proliferation mechanism, we performed Flow Cytometry and Western blot analysis. In Flow Cytometry, S and G2/M phase was significantly decreased, which suggested to arrest cell cycle. In Western blot analysis, cyclin D1 was down-regulated. Conclusion. Iron Depletion by deferasirox have anticancer effect by alone and a synergistic effect in combination with Sorafenib. This result suggested that Iron Depletion therapy can be a novel combination chemotherapy for HCC. Citation Format: Shinichi Urano, Toshiaki Ohara, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Masafumi Kataoka, Nouso Kazuhiro, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron Depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5608. doi:10.1158/1538-7445.AM2013-5608
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A novel synergistic effect of Iron Depletion on antiangiogenic cancer therapy.
International journal of cancer, 2012Co-Authors: Toshiaki Ohara, Shinichi Urano, Kazuhiro Noma, Yasuko Tomono, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Shinichiro Watanabe, Seishi Nishitani, Toshiyoshi FujiwaraAbstract:Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce Iron levels has been shown to suppress tumor growth in vivo. However, Iron Depletion monotherapy by Iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron Depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that Iron Depletion may induce angiogenesis. Therefore, we hypothesized that Iron Depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An Iron-deficient diet and an Iron chelator were used to simulate an Iron-depleted condition. The antitumor effects of Iron Depletion and antiangiogenic therapy were determined on A549 xenograft mice. The Iron-depleted condition produced by an Iron-deficient diet suppressed tumor growth. Tumor tissue from the Iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the Iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An Iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the Iron-depleted antitumor effect. Treatment to deplete Iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.
Shunsuke Kagawa - One of the best experts on this subject based on the ideXlab platform.
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Iron Depletion is a novel therapeutic strategy to target cancer stem cells.
Oncotarget, 2017Co-Authors: Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Yasuko Tomono, Hiroshi Tazawa, Yuki Katsura, Hajime Kashima, Takuya Kato, Shunsuke KagawaAbstract:Adequate Iron levels are essential for human health. However, Iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of Iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, Iron Depletion by the Iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, Iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and Iron Depletion may be a novel therapeutic strategy to target CSCs.
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Iron Depletion enhances the effect of sorafenib in hepatocarcinoma
Cancer biology & therapy, 2016Co-Authors: Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki KimuraAbstract:ABSTACT Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that Iron Depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed Iron Depletion therapy including Iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of Iron Depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum Iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total Iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low Iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar®) and/or deferasirox (EXJADE®) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both Iron Depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by Iron Depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.
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A novel synergistic effect of Iron Depletion on antiangiogenic cancer therapy.
International journal of cancer, 2012Co-Authors: Toshiaki Ohara, Shinichi Urano, Kazuhiro Noma, Yasuko Tomono, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Shinichiro Watanabe, Seishi Nishitani, Toshiyoshi FujiwaraAbstract:Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce Iron levels has been shown to suppress tumor growth in vivo. However, Iron Depletion monotherapy by Iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron Depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that Iron Depletion may induce angiogenesis. Therefore, we hypothesized that Iron Depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An Iron-deficient diet and an Iron chelator were used to simulate an Iron-depleted condition. The antitumor effects of Iron Depletion and antiangiogenic therapy were determined on A549 xenograft mice. The Iron-depleted condition produced by an Iron-deficient diet suppressed tumor growth. Tumor tissue from the Iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the Iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An Iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the Iron-depleted antitumor effect. Treatment to deplete Iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.
Yasuko Tomono - One of the best experts on this subject based on the ideXlab platform.
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Iron Depletion is a novel therapeutic strategy to target cancer stem cells.
Oncotarget, 2017Co-Authors: Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Yasuko Tomono, Hiroshi Tazawa, Yuki Katsura, Hajime Kashima, Takuya Kato, Shunsuke KagawaAbstract:Adequate Iron levels are essential for human health. However, Iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of Iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, Iron Depletion by the Iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, Iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and Iron Depletion may be a novel therapeutic strategy to target CSCs.
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Iron Depletion induced downregulation of n cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer
International Journal of Oncology, 2016Co-Authors: Seishi Nishitani, Toshiaki Ohara, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Yasuhiro Shirakawa, Shinichiro Watanabe, Toshiyoshi FujiwaraAbstract:Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, Iron Depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased Iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased Iron conditions were made using an Iron-Depletion diet in mice and the Iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased Iron conditions. In vitro study showed that decreased Iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased Iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.
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Iron Depletion enhances the effect of sorafenib in hepatocarcinoma
Cancer biology & therapy, 2016Co-Authors: Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki KimuraAbstract:ABSTACT Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that Iron Depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed Iron Depletion therapy including Iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of Iron Depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum Iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total Iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low Iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar®) and/or deferasirox (EXJADE®) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both Iron Depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by Iron Depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.
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Abstract 5608: Iron Depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma.
Experimental and Molecular Therapeutics, 2013Co-Authors: Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Yasuhiro Shirakawa, Shinichiro Watanabe, Masafumi Kataoka, Nouso Kazuhiro, Toshiyoshi FujiwaraAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Purpose. Sorafenib is a multiple kinase inhibitor approved for advanced hepatocellular carcinoma(HCC). However, we couldn't get sufficient effect in clinical use compared to other cancers. Iron metabolism and relationship with cancer cells have been studied for a long time. Iron overload is known to associate with an increased risk of HCC, and the recent study suggests that Iron Depletion can induce anti-cancer effect against HCC. We hypothesized that Iron Depletion enhance the effect of sorafenib and investigated it. Experimental Design. HepG2 (Human hepatocellular liver carcinoma cell line) was used in this study. We used sorafenib and an oral Iron chilator, deferasirox (EXJADE TM). The effects of each agent and combination of both were examined by using cell viability assay. We examined anti-proliferative mechanism in vitro using Flow Cytometry and Western blot analysis. Results. We examined the cell viability of HepG2. Each treatment by sorafenib and deferasirox suppressed the cancer cell proliferation on dose dependent manner. The IC50 values of 48hours of sorafenib was 1.45μM/L,and that of deferasirox was 1.37μM/L. We examined the possibility of combination therapy. The each cell viability of sorafenib 1μM and deferasirox 10μM was 59.4% and 28.1%, the combination one was 21.8%. The combination index was 0.616 in that status, which suggested synergistic effect. To evaluate anti-proliferation mechanism, we performed Flow Cytometry and Western blot analysis. In Flow Cytometry, S and G2/M phase was significantly decreased, which suggested to arrest cell cycle. In Western blot analysis, cyclin D1 was down-regulated. Conclusion. Iron Depletion by deferasirox have anticancer effect by alone and a synergistic effect in combination with Sorafenib. This result suggested that Iron Depletion therapy can be a novel combination chemotherapy for HCC. Citation Format: Shinichi Urano, Toshiaki Ohara, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Masafumi Kataoka, Nouso Kazuhiro, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron Depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5608. doi:10.1158/1538-7445.AM2013-5608
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A novel synergistic effect of Iron Depletion on antiangiogenic cancer therapy.
International journal of cancer, 2012Co-Authors: Toshiaki Ohara, Shinichi Urano, Kazuhiro Noma, Yasuko Tomono, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Shinichiro Watanabe, Seishi Nishitani, Toshiyoshi FujiwaraAbstract:Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce Iron levels has been shown to suppress tumor growth in vivo. However, Iron Depletion monotherapy by Iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron Depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that Iron Depletion may induce angiogenesis. Therefore, we hypothesized that Iron Depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An Iron-deficient diet and an Iron chelator were used to simulate an Iron-depleted condition. The antitumor effects of Iron Depletion and antiangiogenic therapy were determined on A549 xenograft mice. The Iron-depleted condition produced by an Iron-deficient diet suppressed tumor growth. Tumor tissue from the Iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the Iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An Iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the Iron-depleted antitumor effect. Treatment to deplete Iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.
