Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia
© Nasr et al.; licensee BioMed Central Ltd. 2013
Received: 28 August 2013
Accepted: 8 November 2013
Published: 13 November 2013
Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings.
The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA.
Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation.
Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.
KeywordsChemotherapy-induced alopecia eIF4E eIF4A Translation initiation Genetic engineered mouse model Cyclophosphamide
Chemotherapy-induced hair loss (alopecia) is an unmet challenge in clinical oncology and considered one of the most psychologically negative factors in cancer patient care. The psychological impact of chemotherapy-induced alopecia (CIA) is significant. In conjunction with vomiting and nausea, it is among the most feared side-effects of chemotherapy . CIA is seen with alkylating agents (e.g., cyclophosphamide), cytotoxics (e.g., doxorubicin), antimicrotubules (e.g., paclitaxel), and topoisomerase inhibitors (e.g., etoposide) and is a consequence of perturbations of hair-follicle cycling and hair shaft production. No reliable preventative pharmacological approach for CIA is currently available .
Strategies aimed at protecting normal cells from chemotherapeutic agents may offer benefit to prevent CIA. One approach, known as cyclotherapy, aims to selectively and transiently induce cell cycle arrest in normal cells [3, 4]. In proof of principle experiments, the MDM2 antagonist, nutlin-3a, was used to activate p53 and induce a reversible cell-cycle arrest in non-transformed cells - protecting them from S or mitotic phase inhibitors. In contrast, p53-/- tumor cells do not cell cycle arrest and remain susceptible to chemotherapy [5–8]. However, nutlin-3a is not clinically approved, has poor efficacy in vivo, requires a high working concentration (200 mg/kg) in mice [9, 10], and induces cell cycle arrest within a narrow concentration window (between 2 μM and 10 μM) [11, 12]. There is thus a need to identify and test additional small molecules that could be used to entice a cyclotherapy response.
In eukaryotes, suppression of eukaryotic initiation factor (eIF) 4E activity slows G1 progression in yeast  and non-transformed mammalian cells [14, 15]. eIF4E is required for ribosome recruitment during translation initiation and is thought to function through eIF4F, a heterotrimeric complex that consists of (i) eIF4E, a cap-binding protein; (ii) eIF4A, an RNA helicase required for generating a ribosome landing pad; and (iii) eIF4G, a large scaffolding protein . Assembly of eIF4F is regulated by mTOR and is thought to be a nodal point mediating proliferative and survival consequences of increased signaling flux through the PI3K/mTOR pathway . There is thus significant interest in identifying specific inhibitors of eIF4F for assessment as anti-neoplastic agents .
We have recently described the development of a novel inducible RNAi platform in the mouse that combines GFP-coupled shRNA technology with a Flp/FRT recombinase-mediated cassette exchange (RMCE) strategy to generate mice that conditionally express shRNAs [14, 18]. Two strains that we generated enabled inducible and reversible suppression of eIF4E at the organismal level - the effects of which are well tolerated in the mouse [14, 19]. One tissue in which this system shows high eIF4E suppression is in the skin, including hair follicle cells (this study). We therefore envisioned that this model would be useful for assessing a potential role for eIF4E suppression in CIA. Using a well-established protocol for studying CIA in mice , we demonstrate that transient eIF4E suppression prior to chemotherapy protects from CIA by decreasing apoptosis of hair follicle cells. These results provide genetic validation for targeting eIF4E as a mean to reduce CIA.
Doxycycline hydrochloride (Sigma-Aldrich) was dissolved in water at 1 mg/ml with 5% sucrose and supplied to mice in their drinking water. Cyclophosphamide (Sigma-Aldrich) was resuspended in water and stored at 4°C. Nutlin-3a, paclitaxel, nocodazole, and vinorelbine were purchased from Sigma-Aldrich, resuspended in DMSO and stored at -20°C.
Normal human primary fibroblast BJ/TERT (obtained from Dr. Joe Teodoro, McGill University) and MRC5 lung fibroblast cells (ATCC) were cultured in Dulbecco’s modified Eagle’s medium. All media was supplemented with 10% Fetal Bovine Serum (FBS), 100 U/ml penicillin/streptomycin (P/S), and 100 U/ml L-Glutamine. Cells were grown at 37°C and 5% CO2.
Targeting construct and ES cell generation
All mice strains were maintained on a C57BL/6 background. CAGs-RIK mice were crossed to sh4E.389, sh4E.610 and shFLuc.1309 mice  to generate bi-transgenic animals. Mice harboring the shFLuc.1309 allele serve as negative controls whereas using two independent sh4E alleles controls for off-target effects. Mice were genotyped by PCR amplification using the primers for CAGs-RIK (5′-GCTTGTTCTTCACGTGCCAG-3′ and 5′-CTGCTAACCATGTTCATGC-3′), sh4E.389 (5′-AATTACTAGACAACTGGATTGCCT-3′ and 5′-GAAGAACAATCAAGGGTCC-3′), sh4E.610 (5′-GCCACAGATGTATTTAGCTCTAAC-3′ and 5′-GAAGAACAATCAAGGGTCC-3′) and shFLuc.1309 (5′-CACCCTGAAAACTTTGCCCC-3′ and 5′-AAGCCACAGATGTATTAATCAGAGA-3′). All mice strains were maintained on a C57BL/6 background. shRNAmir activation was induced in mice by supplying doxycyline in the drinking water for the indicated periods of time. Dox-supplemented water was changed every 4 days.
Cyclophosphamide (CyP)-induced alopecia
To synchronize hair growth in mice, hair was plucked from the back of mice. Nine days later (time of active hair growth at the anagen VI stage), mice were injected once with 150 mg/kg CyP by intra-peritoneal delivery. In experiments in which sheIF4E or shFLuc miRs were induced, Dox was added to the drinking water for 5 days prior to CyP delivery. Skin sections were harvested at days 12 and 21 post-depilation.
Western blot analysis
For Western blot analysis, cells were lysed in RIPA buffer (50 mM Tris–HCl [pH 7.5], 150 mM NaCl, 1 mM DTT, 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, 0.1 mM phenylmethylsulfonyl fluoride [PMSF], 1 mg/ml each of leupeptin, pepstatin, and aprotinin). Protein lysates were quantified by the Bio-Rad protein assay and 30 μg of proteins was resolved by SDS-PAGE, transferred to PVDF membranes (Millipore), probed with the indicated antibodies, and visualized using enhanced chemiluminescence (ECL) detection (Amersham). The antibodies used for protein expression analysis were directed against eIF4E (Cell Signaling, #9742), p53 (Santa Cruz, #sc-126), and tubulin (Sigma-Aldrich, #T5268).
Ex Vivo treatment studies
Cells were cultured in triplicate in 6-well plates and pre-treated with 5 μM nutlin-3a, 40 nM hippuristanol, 40 nM Cr131-b, 10 μM 4E1RCat, or 10 μM 4E2RCat for 24 hours, followed by removal of the drug and exposure to 50 nM paclitaxel, 200 nM nocodazole, or 40 nM vinorelbine for 48 hours. The compounds were then removed and cells allowed to recover for 5 days. For eIF4E suppression, cells were transfected with siRNA against human eIF4E using Lipofectamine 2000 according to the manufacturer’s recommendations (Sigma-Aldrich). Two days later, cells were exposed to chemotherapy for 48 hrs, after which they were washed and allowed to recover for 5 days. Cells were counted using a Z2 Coulter Counter (Beckman Coulter).
For Giemsa staining, cells were fixed with ice-cold methanol-acetone (1:1 mixture) for 8 min at -20°C, and left to dry at RT. Giemsa solution (Sigma-Aldrich) was diluted 1:20 in PBS buffer and put on cells for 20 min at RT, after which time they were extensively washed with water. Plates were left to dry and visualized by microscopy (AxioScope; Zeiss).
For cell cycle analysis, cells (106 cells/ml) were washed in PBS following compound treatment, fixed in 75% ethanol for 1 hour at 4°C, and stained with 50 mg/ml propidium iodide (Sigma-Aldrich) (containing 3.8 mM sodium citrate, and 500 mg/ml RNase A) for 3 hr at 4°C. DNA content was analyzed by FACScan (BD Biosciences).
Tissues were fixed in 10% neutral buffered formalin for 48 hours before embedding in paraffin and sectioned at 5 μm depth. Sections were dewaxed and rehydrated in a graded series of decreasing alcohol concentrations followed by a water wash. For antigen retrieval, sections were boiled for 15 min in 10 mM citric acid buffer (pH 6.0), followed by a 1 hr incubation in blocking buffer UltraVBlock (Anti-Rabbit HRP/DAB Detection Kit, Abcam), and a 10 min incubation with 3% hydrogen peroxide. Sections were then stained with rabbit primary antibodies against eIF4E (Cell Signaling, #9742, 1:50), GFP (Cell Signaling, # 2555, 1:800), mKate2 (Evrogen, #AB233, 1:800), and cyclin D1 (Cell Signaling, # 2926, 1:100) for 24 hours at 4°C, followed by incubation with biotinylated goat anti-rabbit IgG and streptavadin peroxidase (Anti-Rabbit HRP/DAB Detection Kit, Abcam) for 30 min each. Sections were washed with TBS buffer (0.1 M Tris–HCl (pH 7.5), 0.15 M NaCl) and the signal visualized using 3,3′-diaminobenzidine chromogen. Sections were counterstained with hematoxylin, dehydrated, and mounted using permount. Slides were scanned using an Aperio ScanScope (Aperio, Vista) and signals analyzed using an Aperio ImageScope (Aperio, Vista). Apoptosis was detected by TUNEL using the DeadEnd Fluorometric TUNEL System kit according to the manufacturer’s recommendations (Promega) and TUNEL positive cells were visualized using an Axio Observer fluorescent microscope (Zeiss).
For statistical analysis, unpaired Student t-test with Welch correction was performed using GraphPad InStat version 3.10.
All animal studies were approved by the McGill University Faculty of Medicine Animal Care Committee.
Transient eIF4E suppression protects from CIA
In eukaryotes, modulation of eIF4E can lead to profound consequences on cell cycle progression [13–15]. We therefore sought to directly determine if suppression of eIF4E could protect against CIA. To this end, we took advantage of a recently developed transgenic mouse model in which we could potently suppress eIF4E in hair follicles in an inducible and reversible manner (Figure 1A, B) (Dow, Nasr, Lowe and Pelletier, In Preparation) . As predicted, eIF4E was not suppressed in the hair follicle cells of FLuc.1309/CAGs-RIK mice - a control strain expressing a neutral shRNA to firefly luciferase  (Figure 1B). Importantly, eIF4E suppression could be reversed upon removal of doxycycline (Dox) from the drinking water (Figure 1C). Expression of Kate2 was used in all experiments as a surrogate marker to identify cells expressing rtTA3 (Figure 1D). These experiments highlight the value of CAGs-RIK mice in manipulating eIF4E levels in the hair follicle cells and in using Kate2 to track rtTA3 expression.
Suppression of eIF4E or eIF4A protects against chemotherapy induced cell death
To determine if eIF4F activity had to be inhibited prior to drug treatment to obtain the observed protection, we treated BJ/hTERT cells with nutlin-3a, an eIF4A inhibitor (CR-131-b), or eIF4E:eIF4G interaction inhibitors (4E1RCat and 4E2RCat) concomitantly with PAC, NOCO, or VRL and noticed only a weak protection from cell death (Additional file 2: Figure S2). Taken together, these results indicate that suppression of eIF4E or eIF4A, prior to exposure of cells to cytotoxic agents, affords the greatest degree of protection to chemotherapy-induced cell death.
Alopecia is a frequent side effect of chemotherapy. Previous experiments of CIA in animal models have suggested the use of small molecule modifiers of the cell cycle to protect against chemotherapy. One example is the use of calcitriol (1,25-dihydroxyvitamin D3), known to induce G0/G1 arrest and inhibit DNA synthesis in keratinocytes . Topical administration of calcitriol is able to protect from CIA in a neonatal rat model . Although calcitriol did not fully protect adult mice from CIA, it facilitated hair re-growth by dampening CyP-induced apoptosis [30, 31].
Using a novel transgenic model in which we could inhibit eIF4E expression using inducible shRNA technology, we demonstrated that eIF4E suppression in vivo afforded striking protection to CIA. We note that administration of the eIF4A inhibitor, CR131-b, by intra-venous injection to depilated mice for 5 consecutive days (once a day at 0.2 mg/kg) prior to CyP delivery failed to protect against CIA (data not shown). We attribute this to inadequate delivery of the compound to the intended target cells and these experiments will require more thorough knowledge of the tissue biodistribution and resident half-life of CR131-b in cells of the hair follicles, as well as appropriate surrogate markers to optimize the in vivo dose required to block cell cycling of the intended target cells.
Since inhibition of translation initiation by targeting eIF4F activity leads to accumulation of cells in G1 [14, 32–34], it was reasonable to test the ability of several of the current translation initiation inhibitors in cyclotherapy. To date, several small molecules have been identified that either interfere with eIF4E-cap interaction, eIF4E:eIF4G interaction, or eIF4A helicase activity . We showed that suppression of eIF4E, inhibition of the eIF4A helicase, or disruption of the eIF4E:eIF4G interaction provided significant protection to several chemotherapeutics ex vivo (Figures 5 and 6 and Additional file 1: Figure S1).
Suppression of eIF4E does not lead to global inhibition of protein synthesis but rather to a selective block in the ribosome recruitment phase of a subset of mRNAs. This would suggest that the expression of specific mRNA transcripts is affected in cells of the hair follicles and responsible for the cell cycle and apoptotic block. One potential mechanism is through reduced expression of cyclin D1, a key cell cycle regulator and known eIF4E target [22, 35, 36]. We postulate that the reduction of cyclin D1 in the hair follicles during anagen phase (Figure 3) blocks the majority of cells in G1, thus minimizing cell damage by CyP. This would be consistent with the reduction in apoptosis observed (Figure 3). We have not defined the eIF4E responsive mRNAs responsible for blunting CyP-induced apoptosis but this may simply be a consequence of the G1 block imposed by reductions in cyclin D1. Identifying such transcripts would require an unbiased and genome-wide approach to determining those mRNAs whose translation become altered during eIF4E suppression in the hair follicles. Overall, our results are in line with the principles of cyclotherapy [37, 38].
We do not expect that eIF4E suppression or eIF4F inhibition will interfere with the efficacy of chemotherapy agents due to the absence of effective cell cycle checkpoints in cancer cells. Indeed, in many documented cases, the opposite is observed – that is, enhanced chemotherapy efficacy (synergy) in the presence of compounds that target translation [25, 39–41]. Given that suppressing translation initiation appears a promising approach for cancer therapy, by using small molecule inhibitors of eIF4A or eIF4E:eIF4G interaction or using antisense oligonucleotides (ASOs) against eIF4E , the current results offer an added benefit of targeting translation for chemotherapy – that of protecting against CIA.
In this study, we used a novel murine model that serves as a genetic approximation to drug target inhibition. Targeting the translation initiation factor, eIF4E, in non-transformed cells resulted in an accumulation of cells in G1, affording protection against chemotherapy-induced apoptosis. Suppression eIF4E in cells of the hair follicles provided profound protection against chemotherapy-induced alopecia. This correlated with a reduction in cyclin D1 levels and is consistent with a cyclotherapy response. Our results demonstrate the protective effect that inhibiting translation initiation has on minimizing CIA.
Eukaryotic initiation factor
Mammalian target of rapamycin
Fetal bovine serum
Green fluorescent protein
Recombinase-mediated cassette exchange
Short hairpin RNAs
Cytomegalovirus enhancer/chicken β-actin promoter
Cytomegalovirus enhancer/chicken β-actin promoter–reverse tetracycline transactivator–internal ribosome entry site–Katushka 2
Reverse tetracycline transactivator 3
Sodium dodecyl sulfate
Polyacrylamide gel electrophoresis
Phosphate buffered saline
Polymerase chain reaction
Human telomerase reverse transcriptase
Non-targetting siRNA control
Standard error of the mean
Terminal deoxynucleotidyl transferase dUTP nick end labeling.
This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (MOP-106530) to J.P and from the National Cancer Institute (NCI) (1U01 CA168409) and a Program Project Grant (P01 CA 87497) to S.L.
- de Boer-Dennert M, De Wit R, Schmitz PI, Djontono J, V Beurden V, Stoter G, Verweij J: Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997, 76 (8): 1055-1061. 10.1038/bjc.1997.507.View ArticlePubMedPubMed CentralGoogle Scholar
- Paus R, Haslam IS, Sharov AA, Botchkarev VA: Pathobiology of chemotherapy-induced hair loss. Lancet Oncol. 2013, 14 (2): e50-59. 10.1016/S1470-2045(12)70553-3.View ArticlePubMedGoogle Scholar
- Cheok CF, Verma CS, Baselga J, Lane DP: Translating p53 into the clinic. Nat Rev Clin Oncol. 2011, 8 (1): 25-37. 10.1038/nrclinonc.2010.174.View ArticlePubMedGoogle Scholar
- van Leeuwen IM: Cyclotherapy: opening a therapeutic window in cancer treatment. Oncotarget. 2012, 3 (6): 596-600.View ArticlePubMedPubMed CentralGoogle Scholar
- Cheok CF, Kua N, Kaldis P, Lane DP: Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ. 2010, 17 (9): 1486-1500. 10.1038/cdd.2010.18.View ArticlePubMedGoogle Scholar
- Carvajal D, Tovar C, Yang H, Vu BT, Heimbrook DC, Vassilev LT: Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res. 2005, 65 (5): 1918-1924. 10.1158/0008-5472.CAN-04-3576.View ArticlePubMedGoogle Scholar
- Kranz D, Dobbelstein M: Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. Cancer Res. 2006, 66 (21): 10274-10280. 10.1158/0008-5472.CAN-06-1527.View ArticlePubMedGoogle Scholar
- Tokalov SV, Abolmaali ND: Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment. BMC Cancer. 2010, 10: 57-10.1186/1471-2407-10-57.View ArticlePubMedPubMed CentralGoogle Scholar
- Sur S, Pagliarini R, Bunz F, Rago C, Diaz LA, Kinzler KW, Vogelstein B, Papadopoulos N: A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci USA. 2009, 106 (10): 3964-3969. 10.1073/pnas.0813333106.View ArticlePubMedPubMed CentralGoogle Scholar
- Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, et al: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004, 303 (5659): 844-848. 10.1126/science.1092472.View ArticlePubMedGoogle Scholar
- Verma R, Rigatti MJ, Belinsky GS, Godman CA, Giardina C: DNA damage response to the Mdm2 inhibitor nutlin-3. Biochem Pharmacol. 2010, 79 (4): 565-574. 10.1016/j.bcp.2009.09.020.View ArticlePubMedPubMed CentralGoogle Scholar
- Valentine JM, Kumar S, Moumen A: A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation. BMC Cancer. 2011, 11: 79-10.1186/1471-2407-11-79.View ArticlePubMedPubMed CentralGoogle Scholar
- Brenner C, Nakayama N, Goebl M, Tanaka K, Toh-e A, Matsumoto K: CDC33 encodes mRNA cap-binding protein eIF-4E of Saccharomyces cerevisiae. Mol Cell Biol. 1988, 8 (8): 3556-3559.View ArticlePubMedPubMed CentralGoogle Scholar
- Lin CJ, Nasr Z, Premsrirut PK, Porco JA, Hippo Y, Lowe SW, Pelletier J: Targeting Synthetic Lethal Interactions between Myc and the eIF4F Complex Impedes Tumorigenesis. Cell Rep. 2012, 1 (4): 325-333. 10.1016/j.celrep.2012.02.010.View ArticlePubMedPubMed CentralGoogle Scholar
- Lynch M, Fitzgerald C, Johnston KA, Wang S, Schmidt EV: Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. J Biol Chem. 2004, 279 (5): 3327-3339.View ArticlePubMedGoogle Scholar
- Hinnebusch AG, Lorsch JR: The mechanism of eukaryotic translation initiation: new insights and challenges. Protein Synthesis and Translational Control. Edited by: John WB, Hershey, Nahum S, Michael B. 2012, Mathews: Cold Spring Harbor Laboratory Press, 29-53.Google Scholar
- Malina A, Mills JR, Pelletier J: Emerging therapeutics targeting mRNA translation. Protein Synthesis and Translational Control. Edited by: John WB, Hershey, Nahum S, Michael B. 2012, Mathews: Cold Spring Harbor Laboratory Press, 327-343.Google Scholar
- Premsrirut PK, Dow LE, Kim SY, Camiolo M, Malone CD, Miething C, Scuoppo C, Zuber J, Dickins RA, Kogan SC, et al: A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell. 2011, 145 (1): 145-158. 10.1016/j.cell.2011.03.012.View ArticlePubMedPubMed CentralGoogle Scholar
- Cencic R, Carrier M, Galicia-Vazquez G, Bordeleau ME, Sukarieh R, Bourdeau A, Brem B, Teodoro JG, Greger H, Tremblay ML, et al: Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS ONE. 2009, 4 (4): e5223-10.1371/journal.pone.0005223.View ArticlePubMedPubMed CentralGoogle Scholar
- Paus R, Handjiski B, Eichmuller S, Czarnetzki BM: Chemotherapy-induced alopecia in mice. Induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by dexamethasone. Am J Pathol. 1994, 144 (4): 719-734.PubMedPubMed CentralGoogle Scholar
- Lin CJ, Cencic R, Mills JR, Robert F, Pelletier J: c-Myc and eIF4F are components of a feedforward loop that links transcription and translation. Cancer Res. 2008, 68 (13): 5326-5334. 10.1158/0008-5472.CAN-07-5876.View ArticlePubMedGoogle Scholar
- Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N: Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc Natl Acad Sci USA. 1996, 93 (3): 1065-1070. 10.1073/pnas.93.3.1065.View ArticlePubMedPubMed CentralGoogle Scholar
- Hendrix S, Handjiski B, Peters EM, Paus R: A guide to assessing damage response pathways of the hair follicle: lessons from cyclophosphamide-induced alopecia in mice. J Invest Dermatol. 2005, 125 (1): 42-51. 10.1111/j.0022-202X.2005.23787.x.View ArticlePubMedGoogle Scholar
- Rodrigo CM, Cencic R, Roche SP, Pelletier J, Porco JA: Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies. J Med Chem. 2012, 55 (1): 558-562. 10.1021/jm201263k.View ArticlePubMedGoogle Scholar
- Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, Brem B, Greger H, Lowe SW, Porco JA, et al: Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008, 118 (7): 2651-2660.PubMedPubMed CentralGoogle Scholar
- Bordeleau M-E, Mori A, Oberer M, Lindqvist L, Chard LS, Higa T, Belsham GJ, Wagner G, Tanaka J, Pelletier J: Functional Characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat Chem Biol. 2006, 2: 213-220. 10.1038/nchembio776.View ArticlePubMedGoogle Scholar
- Cencic R, Hall DR, Robert F, Du Y, Min J, Li L, Qui M, Lewis I, Kurtkaya S, Dingledine R, et al: Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc Natl Acad Sci USA. 2011, 108 (3): 1046-1051. 10.1073/pnas.1011477108.View ArticlePubMedGoogle Scholar
- Wang J, Lu Z, Au JL: Protection against chemotherapy-induced alopecia. Pharm Res. 2006, 23 (11): 2505-2514. 10.1007/s11095-006-9105-3.View ArticlePubMedGoogle Scholar
- Jimenez JJ, Yunis AA: Protection from chemotherapy-induced alopecia by 1,25-dihydroxyvitamin D3. Cancer Res. 1992, 52 (18): 5123-5125.PubMedGoogle Scholar
- Paus R, Schilli MB, Handjiski B, Menrad A, Henz BM, Plonka P: Topical calcitriol enhances normal hair regrowth but does not prevent chemotherapy-induced alopecia in mice. Cancer Res. 1996, 56 (19): 4438-4443.PubMedGoogle Scholar
- Schilli MB, Paus R, Menrad A: Reduction of intrafollicular apoptosis in chemotherapy-induced alopecia by topical calcitriol-analogs. J Invest Dermatol. 1998, 111 (4): 598-604. 10.1046/j.1523-1747.1998.00350.x.View ArticlePubMedGoogle Scholar
- Nasr Z, Robert F, Porco JA, Muller WJ, Pelletier J: eIF4F suppression in breast cancer affects maintenance and progression. Oncogene. 2013, 32 (7): 861-871. 10.1038/onc.2012.105.View ArticlePubMedGoogle Scholar
- Zhou FF, Yan M, Guo GF, Wang F, Qiu HJ, Zheng FM, Zhang Y, Liu Q, Zhu XF, Xia LP: Knockdown of eIF4E suppresses cell growth and migration, enhances chemosensitivity and correlates with increase in Bax/Bcl-2 ratio in triple-negative breast cancer cells. Med Oncol. 2011, 28 (4): 1302-1307. 10.1007/s12032-010-9630-0.View ArticlePubMedGoogle Scholar
- Soni A, Akcakanat A, Singh G, Luyimbazi D, Zheng Y, Kim D, Gonzalez-Angulo A, Meric-Bernstam F: eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther. 2008, 7 (7): 1782-1788. 10.1158/1535-7163.MCT-07-2357.View ArticlePubMedPubMed CentralGoogle Scholar
- Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM: Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem. 1995, 270 (36): 21176-21180. 10.1074/jbc.270.36.21176.View ArticlePubMedGoogle Scholar
- Rosenwald IB, Lazaris-Karatzas A, Sonenberg N, Schmidt EV: Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol. 1993, 13 (12): 7358-7363.View ArticlePubMedPubMed CentralGoogle Scholar
- Blagosklonny MV, Darzynkiewicz Z: Cyclotherapy: protection of normal cells and unshielding of cancer cells. Cell Cycle. 2002, 1 (6): 375-382. 10.4161/cc.1.6.259.View ArticlePubMedGoogle Scholar
- Keyomarsi K, Pardee AB: Selective protection of normal proliferating cells against the toxic effects of chemotherapeutic agents. Prog Cell Cycle Res. 2003, 5: 527-532.PubMedGoogle Scholar
- Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW: Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004, 428 (6980): 332-337. 10.1038/nature02369.View ArticlePubMedGoogle Scholar
- Cencic R, Robert F, Galicia-Vazquez G, Malina A, Ravindar K, Somaiah R, Pierre P, Tanaka J, Deslongchamps P, Pelletier J: Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A. Blood Cancer J. 2013, 3: e128-10.1038/bcj.2013.25.View ArticlePubMedPubMed CentralGoogle Scholar
- Robert F, Carrier M, Rawe S, Chen S, Lowe S, Pelletier J: Altering chemosensitivity by modulating translation elongation. PLoS ONE. 2009, 4 (5): e5428-10.1371/journal.pone.0005428.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/2050-6511/14/58/prepub
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