scholarly journals Proliferation impairs cell viability via energy depletion

2020 ◽  
Author(s):  
Pierre Galichon ◽  
Morgane Lannoy ◽  
Li Li ◽  
Sophie Vandermeersch ◽  
David Legouis ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cell Survival ◽  
Cell Lines ◽  
Renal Outcome ◽  
Energy Status ◽  
Transcriptomic Data ◽  
Intracellular Atp ◽  
Expression Of Genes ◽  
Oxidative Phosphorylation Pathway

ABSTRACTIntroductionProliferation is essential to the development of all living organisms and to the replacement of dead cells in injured organs. Proliferation is tightly regulated, and loss of proliferation control is a hallmark of cancer. Thus, cell proliferation and cell survival are closely interconnected to contribute to organ homeostasis or tumor development. Given the central role of energy homeostasis in cell survival, and the fact that proliferation increases negentropy, we hypothesized that proliferation might affect the intracellular ATP/ADP ratio, a robust readout of the cellular energy status.MethodsWe analyzed transcriptomic data and cytotoxicity assessment from tumor cell lines challenged with a panel of chemotherapies. We then analyzed the effect of proliferation on the viability and on the intracellular ATP/ADP ratio of epithelial cell lines challenged with toxic or energetic stresses. Finally, we studied transcriptomic data from both tumors and injured or recovering kidneys, and computed indexes for proliferation, and nuclear vs mitochondrially encoded oxidative phosphorylation genes.ResultsHere we found that proliferation is associated with decreased survival after toxic or energetic stresses in both cancer and epithelial cells. In vitro, we found that ATP/ADP ratio was tightly regulated throughout the cell cycle, and that proliferation was instrumental to an overall decrease in intracellular ATP/ADP ratio. In vivo, we found that the expression of genes of the oxidative phosphorylation pathway (OXPHOS) was correlated with proliferation in cancer. In injured kidneys, proliferation was also associated with increased expression of genes of the oxidative phosphorylation pathway encoded in the nucleus, but mitochondrially-encoded genes were strongly decreased, suggesting the coexistence of a passive mitochondrial injury and an adaptative nuclear response with opposite effects on OXPHOS. Increased proliferation and decreased expression of mitochondrially-encoded genes of the oxidative phosphorylation pathway were associated with a poor renal outcome. In sum, we show that proliferation is an energy demanding process impairing the cellular ability to cope with a toxic or ischemic injury.

scholarly journals Focal Adhesion Kinase Inhibition Contributes to Tumor Cell Survival and Motility in Neuroblastoma Patient-Derived Xenografts

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura L. Stafman ◽  
Adele P. Williams ◽  
Raoud Marayati ◽  
Jamie M. Aye ◽  
Hooper R. Markert ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
Human Condition ◽  
Migration And Invasion ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cycle Arrest

Abstract Patient-derived xenografts (PDXs) provide an opportunity to evaluate the effects of therapies in an environment that more closely resembles the human condition than that seen with long-term passage cell lines. In the current studies, we investigated the effects of FAK inhibition on two neuroblastoma PDXs in vitro. Cells were treated with two small molecule inhibitors of FAK, PF-573,228 (PF) and 1,2,4,5-benzentetraamine tetrahydrochloride (Y15). Following FAK inhibition, cell survival and proliferation decreased significantly and cell cycle arrest was seen in both cell lines. Migration and invasion assays were used to determine the effect of FAK inhibition on cell motility, which decreased significantly in both cell lines in the presence of either inhibitor. Finally, tumor cell stemness following FAK inhibition was evaluated with extreme limiting dilution assays as well as with immunoblotting and quantitative real-time PCR for the expression of stem cell markers. FAK inhibition decreased formation of tumorspheres and resulted in a corresponding decrease in established stem cell markers. FAK inhibition decreased many characteristics of the malignant phenotype, including cancer stem cell like features in neuroblastoma PDXs, making FAK a candidate for further investigation as a potential target for neuroblastoma therapy.

Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4166-4178 ◽  
Author(s):  
Toni Portis ◽  
Patricia Dyck ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Gene Transcription ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Expression Of Genes ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) is associated with the development of a variety of malignancies, including Hodgkin lymphoma. One of the few viral transcripts expressed in EBV-positive Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma is latent membrane protein 2A (LMP2A). This viral protein blocks B-cell receptor (BCR)-signaling in vitro. Furthermore, expression of LMP2A in developing B cells in vivo induces a global down-regulation of genes necessary for proper B-cell development. In this study we have analyzed gene transcription in primary B cells from LMP2A transgenic mice, LMP2A-expressing human B-cell lines, and LMP2A-positive and -negative EBV-infected lymphoblastoid cell lines (LCLs). We demonstrate that LMP2A increases the expression of genes associated with cell cycle induction and inhibition of apoptosis, alters the expression of genes involved in DNA and RNA metabolism, and decreases the expression of B-cell-specific factors and genes associated with immunity. Furthermore, many alterations in gene expression induced by LMP2A are similar to those recently described in HRS cells of Hodgkin lymphoma and activated, proliferating germinal center centroblasts/centrocytes. These correlations suggest that LMP2A expression in EBV-infected B cells may lead to the induction and maintenance of an activated, proliferative state that could ultimately result in the development of Hodgkin lymphoma. (Blood. 2003;102: 4166-4178)

scholarly journals KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors

2020 ◽  
Vol 2 (Supplement_1) ◽  
pp. i62-i74 ◽  
Author(s):  
Ernest Terribas ◽  
Marco Fernández ◽  
Helena Mazuelas ◽  
Juana Fernández-Rodríguez ◽  
Josep Biayna ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Cell Survival ◽  
Cell Lines ◽  
Nerve Sheath Tumor ◽  
Division Rate ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Genetic Suppression ◽  
The Impact

Abstract Background Malignant peripheral nerve sheath tumor (MPNST) constitutes the leading cause of neurofibromatosis type 1–related mortality. MPNSTs contain highly rearranged hyperploid genomes and exhibit a high division rate and aggressiveness. We have studied in vitro whether the mitotic kinesins KIF11, KIF15, and KIF23 have a functional role in maintaining MPNST cell survival and can represent potential therapeutic vulnerabilities. Methods We studied the expression of kinesin mRNAs and proteins in tumors and cell lines and used several in vitro functional assays to analyze the impact of kinesin genetic suppression (KIF15, KIF23) and drug inhibition (KIF11) in MPNST cells. We also performed in vitro combined treatments targeting KIF11 together with other described MPNST targets. Results The studied kinesins were overexpressed in MPNST samples. KIF15 and KIF23 were required for the survival of MPNST cell lines, which were also more sensitive than benign control fibroblasts to the KIF11 inhibitors ispinesib and ARRY-520. Co-targeting KIF11 and BRD4 with ARRY-520 and JQ1 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts. In addition, genetic suppression of KIF15 conferred an increased sensitivity to KIF11 inhibitors alone or in combination with JQ1. Conclusions The mitotic spindle kinesins KIF11 and KIF15 and the cytokinetic kinesin KIF23 play a clear role in maintaining MPNST cell survival and may represent potential therapeutic vulnerabilities. Although further in vivo evidences are still mandatory, we propose a simultaneous suppression of KIF11, KIF15, and BRD4 as a potential therapy for MPNSTs.

scholarly journals Inhibition of Mitochondrial Translation By the Marine Natural Product Elatol Shows Potent Antileukemia Activity

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4342-4342
Author(s):  
Priyanka Maiti ◽  
Tyler A. Cunningham ◽  
Antonio Barrientos ◽  
Jonathan H. Schatz
Keyword(s):  
Stem Cells ◽  
Protein Synthesis ◽  
Oxidative Phosphorylation ◽  
Cell Lines ◽  
Leukemia Cell ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Mitochondrial Translation ◽  
Signaling Inhibitors

Abstract Targeted signaling inhibitors for hematologic malignancies may lead to limited clinical efficacy due to the outgrowth of subpopulations with alternative pathways independent of the drug target. Relapse/refractory disease that results from treatment with targeted signaling inhibitors is a major hurdle in obtaining curative responses. Interestingly, work over the past decade or more has shown that chronic myelogenous leukemia (CML) stem cells (CD34+CD38-) are resistant to targeted signaling inhibitors, such as the BCR-ABL kinase class of inhibitors, often a problematic source of resistance leading to residual disease that may precipitate later progression (Hamilton et al., 2012). Recent studies have shown that some forms of lymphoma and leukemia cell have an energy metabolism highly dependent on mitochondrial oxidative phosphorylation (Ashton et al., 2018). Tigecycline, a US FDA approved antibiotic, has been shown to inhibit synthesis of mitochondrion-encoded proteins due to the similarity of bacterial and mitochondrial ribosomes, leading to selective lethality in hematologic malignancies reliant on enhanced oxidative phosphorylation (Norberg et al., 2017). Indeed, it was established that CML stem cells are reliant on upregulated oxidative phosphorylation, and combination treatment with the tyrosine-kinase inhibitor (TKI) imatinib and tigecycline eradicated therapy-resistant CML, both in vitro and in animal models (Kuntz et al., 2017). We have previously reported that elatol, the major compound from the red alga Laurencia microcladia, is effective against several non-Hodgkin lymphomas and primary chronic myelogenous leukemia cells (Peters et al., 2018). In vitro studies showed that elatol inhibits eIF4A1 helicase activity, suppressing cytoplasmic cap-dependent translation initiation. Further assessments using 35-S-methionine incorporation in HEK293T cells with or without single-digit micromolar concentrations of elatol for short time periods revealed strong downregulation of mitochondrion-encoded proteins as in Figure 1, (with no effect on mitochondrial transcription). This was confirmed in CML and acute lymphoblastic leukemia (ALL) cell lines whose 24-hour elatol LD50 ranged from high nanomolar to low micromolar concentrations. This potency was 10-40x higher than for tigecycline in side-by-side comparisons across several leukemia cell lines when compared at 72h. Additionally, we established that elatol does not affect integrity of small and large mitochondrial ribosomal units through sedimentation property analysis using sucrose gradients. Although the specific target on the mitochondrial translation apparatus remains elusive, we have uncovered that its mechanism of action differs from that of chloramphenicol, which inhibits translation elongation. In summary, we have performed proof-of-concept studies using HEK293T and HeLa cell lines, isolated mitochondria from HEK293T, and CML and ALL cell lines to reveal that elatol is a potent inhibitor of mitochondrial protein synthesis at concentrations that do not affect cytoplasmic protein synthesis and that this mechanism differs from chloramphenicol. Tigecycline's compelling preclinical data in combination with TKI informed design of a pending clinical trial (NCT02883036). Elatol's greatly improved potency provide a potential starting point for further optimization of this paradigm. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals UBR5 Mutations in Mantle Cell Lymphoma Lead to Increased Proliferation through a Cyclin D1-Dependent Mechanism

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2849-2849
Author(s):  
Olga Kutovaya ◽  
Stacy Hung ◽  
Elena Viganò ◽  
Adele Telenius ◽  
Bruce W Woolcock ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Gene Mutations ◽  
Non Hodgkin Lymphoma ◽  
Expression Of Genes ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma, with patient outcomes inferior to most other lymphoma subtypes. Recent progress in describing recurrent somatic gene mutations has led to a better understanding of MCL pathogenesis. However, the functional and clinical implications of many alterations remain to be elucidated. Here, to uncover the role of recurrent UBR5 gene mutations in lymphomagenesis, we studied a cohort of 248 MCL patients by targeted sequencing and performed genome editing of MCL-derived cell lines to investigate UBR5-mutation associated phenotypes in vitro. We identified deleterious UBR5 exon 58 hotspot mutations in 8% of MCL patients, all of which were mutually exclusive with CCND1 mutations. Proteomics analysis of Granta-519 and Jeko-1 cell lines with engineered UBR5 exon 58 indel mutations showed differential expression of genes involved in cell cycle and ubiquitination, and led to the discovery of decreased phosphorylation of CCND1 in the UBR5-mutated lines. Accordingly, in vitro studies of engineered genome-edited Granta-519, Jeko-1 and Mino cells revealed accumulation of cells in the S phase of the cell cycle, increased phosphorylation of retinoblastoma protein (Rb), and increased lymphoma cell proliferation. Our results demonstrate that UBR5 mutations, in addition to the hallmark t(11;14) translocation drive proliferation of MCL cells, potentially rendering mutation-carrying cells more sensitive to targeted therapies. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Roche: Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding. Steidl:Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Tioma: Research Funding.

scholarly journals Metabolic Cooperation in the Ovarian Follicle

2020 ◽  
pp. 33-48
Author(s):  
J. FONTANA ◽  
S. MARTÍNKOVÁ ◽  
J. PETR ◽  
T. ŽALMANOVÁ ◽  
J. TRNKA
Keyword(s):  
Ovarian Follicle ◽  
Cumulus Cells ◽  
Point Of View ◽  
Energy Status ◽  
Metabolic Cooperation ◽  
Energy Substrates ◽  
Vitro Fertilization ◽  
Oxidative Phosphorylation Pathway ◽  
Underlying Mechanisms

Granulosa cells (GCs) are somatic cells essential for establishing and maintaining bi-directional communication with the oocytes. This connection has a profound importance for the delivery of energy substrates, structural components and ions to the maturing oocyte through gap junctions. Cumulus cells, group of closely associated GCs, surround the oocyte and can diminished the effect of harmful environmental insults. Both GCs and oocytes prefer different energy substrates in their cellular metabolism: GCs are more glycolytic, whereas oocytes rely more on oxidative phosphorylation pathway. The interconnection of these cells is emphasized by the fact that GCs supply oocytes with intermediates produced in glycolysis. The number of GCs surrounding the oocyte and their age affect the energy status of oocytes. This review summarises available studies collaboration of cellular types in the ovarian follicle from the point of view of energy metabolism, signaling and protection of toxic insults. A deeper knowledge of the underlying mechanisms is crucial for better methods to prevent and treat infertility and to improve the technology of in vitro fertilization.

scholarly journals Impact of Superparamagnetic Iron Oxide Nanoparticles on In Vitro and In Vivo Radiosensitisation of Cancer Cells

2020 ◽  
Author(s):  
Emily Russell ◽  
Victoria Dunne ◽  
Ben Russell ◽  
Hibaaq Mohamud ◽  
Mihaela Ghita ◽  
...  
Keyword(s):  
Dna Damage ◽  
Iron Oxide ◽  
Cell Survival ◽  
Cell Lines ◽  
Tumour Growth ◽  
Superparamagnetic Iron Oxide ◽  
Oxide Nanoparticles ◽  
U87 Cells

Abstract PurposeThe recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. This study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. MethodsSPION uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Measured dose enhancement factors (DEFs) were with the predicted DEFs based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. ResultsSPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 hr post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 hr exposure to 0.1 mM SPIONs. There was also a 30.1 % increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with DEFs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (p < 0.05). ConclusionsSPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

Heat Shock Protein 90 Inhibitor NVP-AUY922 Has Potent Anti-Tumor Activity With Adult T-Cell Leukemia-Lymphoma Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1829-1829
Author(s):  
Hiroaki Taniguchi ◽  
Hiroo Hasegawa ◽  
Daisuke Sasaki ◽  
Koji Ando ◽  
Yasushi Sawayama ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Adult T Cell Leukemia ◽  
Pim Kinases ◽  
Client Proteins

Abstract Background Adult T-cell leukemia-lymphoma (ATL) is a chemo-resistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. The HSP90 inhibitor 17-AAG, derived from geldanamycin, has potent antitumor activity against ATL. However, geldanamycin derivatives have several limitations, including poor solubility, formulation difficulties, and severe hepatotoxicity in clinical settings, which have prompted development of second generation synthetic HSP90 inhibitors including NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor that inhibits the ATPase activity of HSP90. AUY922 has shown nanomolar efficacy against a wide range of human cancer cells in vitro and also inhibits progression of a variety of tumors in vivo. Phase I/II studies of AUY922 with advanced solid tumors and hematological malignancies are presently underway. Here, we studied the effects of AUY922 on ATL in vitro and in vivo. Results We initially analyzed the effects of AUY922 (Novartis Pharmaceuticals) on survival of ATL-derived cell lines (KK1, SO4, LM-Y1, KOB, ST1) and HTLV-I-infected T-cell lines (MT2, HuT102). Cells cultured with various concentrations of AUY922 for 72 hours showed survival suppression in a dose-dependent manner in MTS assay findings. The concentrations of AUY922 required to inhibit cell survival by 50% (IC50) varied from 12.5 to 25.0 nM. We also found that the inhibitory effect of AUY was superior to that of 17-AAG. We further assessed AUY922-induced cell survival inhibition with peripheral blood mononuclear cells (PBMCs) obtained from patients with ATL and healthy donors. AUY922 induced apparent cell survival suppression in primary ATL cells, but not in normal PBMCs, while FACS analysis revealed that AUY922 induced cell-cycle arrest and apoptosis in these cell lines. Interestingly, AUY922 induced down-regulation of PIM kinases, which was confirmed by DNA microarray, qRT-PCR, and WB analysis results. Furthermore, SGI-1776, a PIM kinase inhibitor, successfully induced cell survival suppression in ATL and HTLV-1 infected cell lines in both dose- and cell-dependent manners. To elucidate the molecular mechanisms of cytotoxicity, we also examined the expressions of several client proteins using WB analysis. AUY922 treatment led to strong up-regulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease of HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including p-Akt, Akt, IκBα, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin. In a xenograft model created with C.B-17/Icr-SCID mice, intraperitoneal administration of the vehicle or AUY922 was given after injection of HuT102 cells. In the control mice, bulky tumors grew within 4 weeks, whereas daily administrations of AUY922 significantly impaired tumor growth. Conclusion Together, our findings suggest that AUY922 may be an effective therapeutic agent for ATL and PIM kinases are a novel therapeutic target. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 577 ◽  
Author(s):  
Maya Idriss ◽  
Mohammad Hassan Hodroj ◽  
Rajaa Fakhoury ◽  
Sandra Rizk
Keyword(s):  
Breast Cancer ◽  
Vitamin E ◽  
Cell Survival ◽  
Cell Lines ◽  
Breast Adenocarcinoma ◽  
G1 Arrest ◽  
Human Breast ◽  
Gamma Tocotrienol ◽  
Survival Proteins

Studies on tocotrienols have progressively revealed the benefits of these vitamin E isoforms on human health. Beta-tocotrienol (beta-T3) is known to be less available in nature compared to other vitamin E members, which may explain the restricted number of studies on beta-T3. In the present study, we aim to investigate the anti-proliferative effects and the pro-apoptotic mechanisms of beta-T3 on two human breast adenocarcinoma cell lines MDA-MB-231 and MCF7. To assess cell viability, both cell lines were incubated for 24 and 48 h, with different concentrations of beta-T3 and gamma-T3, the latter being a widely studied vitamin E isoform with potent anti-cancerous properties. Cell cycle progression and apoptosis induction upon treatment with various concentrations of the beta-T3 isoform were assessed. The effect of beta-T3 on the expression level of several apoptosis-related proteins p53, cytochrome C, cleaved-PARP-1, Bax, Bcl-2, and caspase-3, in addition to key cell survival proteins p-PI3K and p-GSK-3 α/β was determined using western blot analysis. Beta-tocotrienol exhibited a significantly more potent anti-proliferative effect than gamma-tocotrienol on both cell lines regardless of their hormonal receptor status. Beta-T3 induced a mild G1 arrest on both cell lines, and triggered a mitochondrial stress-mediated apoptotic response in MDA-MB-231 cells. Mechanistically, beta-T3′s anti-neoplastic activity involved the downregulation of phosphorylated PI3K and GSK-3 cell survival proteins. These findings suggest that vitamin E beta-T3 should be considered as a promising anti-cancer agent, more effective than gamma-T3 for treating human breast cancer and deserves to be further studied to investigate its effects in vitro and on other cancer types.

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