scholarly journals Selective Targeting of Class1 Histone Deacetylase (HDAC) Isoforms by a Novel Inhibitor SBAK-GHA Potently Resist Leukemogenesis

2020 ◽  
Author(s):  
Javeed Ahmad Bhat ◽  
Nawab John Dar ◽  
Mudassier Ahmad ◽  
Mubashir Javed Mintoo ◽  
Rauf Ahmad Najar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Acetylation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Leukemic Cell ◽  
Class I ◽  
Leukemic Cell Lines ◽  
Cycle Arrest

Abstract Background: Acute promyelocytic leukemia (APL) and acute lymphoblastic leukaemia (ALL) are often presented with loss of H4K16 monoacetylation (ac) and H4K20 trimethylation (3Me) due to increased activity of Class I HDAC’s. In the current study we explored the efficacy and mechanistic basis of a novel Class I HDAC inhibitor SBAK-GHA across different leukemic cell lines and characterised the distinct acetylation pattern on histone H3 and H4.Methods: We initially performed general and class specific HDAC enzyme activity assays to establish the effect of our lead molecule SBAK-GHA. Following, we have probed various acetylation sites to understand a thorough acetylation profile of various leukemic cell lines by immunoblotting. Next, to understand the effect of various Class 1 HDAC isoforms on acetylation levels of hallmark proteins in leukaemia; lentiviral knockdown approach was carried out. In addition, cell cycle analysis was also done to distinguish the pattern of cell cycle phase arrest, followed by Chip-qPCR studies of various cyclins and their relationship with cell cycle arrest. Finally, an in vivo study was performed to confirm the anti-leukemic activity of SBAK-GHA by using specific leukaemia models.Results: SBAK-GHA showed class I HDAC inhibitor activity specifically targeting HDAC 2. SBAK-GHA treatment upregulates H4K16 ac and H4K20 me3 in variety of leukemic cell lines. Similar results were found during knock down of HDAC2 in leukemic cell lines. Moreover, we also observed a coherence of events like cell cycle arrest across different cell types of leukemias and modulation in the levels of acetylation across different cyclin promoters. Further on, studies in various in vivo cancer models demonstrated SBAK-GHA to be highly selective towards lymphocytic leukaemia.Conclusion: Our data provided a basic overview of relationship between different class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia. Our study here presented multiple evidences regarding SBAK-GHA as a novel HDAC2 inhibitor. SBAK-GHA resist leukemogenesis mainly by inducing the repressed H4K16 ac and H4K20 me3. Further, the results in present study had established a relationship between class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia.

Ligand Activation of FLT3 Induces Cell Cycle Arrest in Acute Lymphoblastic Leukemia with 11q23 Translocation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1888-1888
Author(s):  
Yoshiyuki Furuichi ◽  
Kanji Sugita ◽  
Takeshi Inukai ◽  
Kumiko Goi ◽  
Kazuya Takahashi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Hematopoietic Stem ◽  
Leukemic Cell Lines ◽  
Cycle Arrest

Abstract A fms-like kinase (FLT3) is widely known to be involved in proliferation of normal hematopoietic stem cells and precursors. Acute lymphoblastic leukemia (ALL) with 11q23 translocation, often found in infantile leukemia with very poor prognosis, is thought to be derived from a population of cells at the developmental stage very close to hematopoietic stem cells, and was recently shown that they express FLT3 at high levels compared with other types of leukemia. In the present study, we examined the effects of FLT3 ligand (FL) on leukemia cells with or without 11q23 translocation to evaluate a biological implication of the FLT3/FL interaction in ALL. Three of 8 leukemic cell lines without 11q23 translocation showed a proliferative response to FL in the 3H-thymidine uptake assays. However, five of 7 B-precursor leukemic cell lines with 11q23 translocation, unexpectedly, showed an inhibitory response (23-69% inhibition) to FL in a dose-dependent manner (1–20ng/ml), although the special cell line with D835 mutation in FLT3 (KOCL-33) was not affected by the addition of FL. This inhibitory effect was almost abrogated in the presence of a FLT-3 kinase inhibitor PKC412. Inhibition of 3H-thymidine uptakes were not due to induction of apoptosis but due to induction of the Go/G1 arrest. This cell cycle arrest was mediated, at least in part, by a marked up-regulation of p27 due to suppression of its degradation, and promoted resistance of cell lines to radiation-induced apoptosis. Of interest, the addition of FL induced a complete disappearance of constitutive phosphorylation of STAT5 but upregulated phosphorylation of MAPK and Akt. These results suggest that the FLT3/FL interaction in ALL with 11q23 translocation transmits the inhibitory signal specifically to the JAK/STAT pathway via the kinase activity of FLT3, in the process of which the JAK/STAT-specific inhibitory molecules such as SOCS-2 and CIS-1 may be implicated.

scholarly journals Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

2020 ◽  
Vol 13 ◽  
pp. 175628481989543
Author(s):  
Amanda Braga Bona ◽  
Danielle Queiroz Calcagno ◽  
Helem Ferreira Ribeiro ◽  
José Augusto Pereira Carneiro Muniz ◽  
Giovanny Rebouças Pinto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Gastric Carcinogenesis ◽  
In Vivo Experiments ◽  
Cycle Arrest

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

scholarly journals Cyperus articulatus L. (Cyperaceae) Rhizome Essential Oil Causes Cell Cycle Arrest in the G2/M Phase and Cell Death in HepG2 Cells and Inhibits the Development of Tumors in a Xenograft Model

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2687
Author(s):  
Mateus L. Nogueira ◽  
Emilly J. S. P. de Lima ◽  
Asenate A. X. Adrião ◽  
Sheila S. Fontes ◽  
Valdenizia R. Silva ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gas Chromatography ◽  
Cell Death ◽  
Liver Cancer ◽  
Essential Oil ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hepg2 Cells ◽  
Cycle Arrest

Cyperus articulatus L. (Cyperaceae), popularly known in Brazil as “priprioca” or “piriprioca”, is a tropical and subtropical plant used in popular medical practices to treat many diseases, including cancer. In this study, C. articulatus rhizome essential oil (EO), collected from the Brazilian Amazon rainforest, was addressed in relation to its chemical composition, induction of cell death in vitro and inhibition of tumor development in vivo, using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC-FID), respectively. The cytotoxic activity of EO was examined against five cancer cell lines (HepG2, HCT116, MCF-7, HL-60 and B16-F10) and one non-cancerous one (MRC-5) using the Alamar blue assay. Cell cycle distribution and cell death were investigated using flow cytometry in HepG2 cells treated with EO after 24, 48 and 72 h of incubation. The cells were also stained with May–Grunwald–Giemsa to analyze the morphological changes. The anti-liver-cancer activity of EO in vivo was evaluated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The main representative substances of this EO sample were muskatone (11.6%), cyclocolorenone (10.3%), α-pinene (8.26%), pogostol (6.36%), α-copaene (4.83%) and caryophyllene oxide (4.82%). EO showed IC50 values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC50 value for non-cancerous of 46.0 µg/mL (MRC-5), showing selectivity indices below 2-fold for all cancer cells tested. HepG2 cells treated with EO showed cell cycle arrest at G2/M along with internucleosomal DNA fragmentation. The morphological alterations included cell shrinkage and chromatin condensation. Treatment with EO also increased the percentage of apoptotic-like cells. The in vivo tumor mass inhibition rates of EO were 46.5–50.0%. The results obtained indicate the anti-liver-cancer potential of C. articulatus rhizome EO.

scholarly journals Effects of annexin A1 on apoptosis and cell cycle arrest in human leukemic cell lines

2019 ◽  
Vol 69 (1) ◽  
pp. 75-86 ◽  
Author(s):  
Affidah Sabran ◽  
Endang Kumolosasi ◽  
Ibrahim Jantan
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Leukemic Cell ◽  
Jurkat Cells ◽  
G1 Phase ◽  
U937 Cells ◽  
Annexin A1 ◽  
Leukemic Cell Lines ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract Recent studies suggest that annexin A1 (ANXA1) promotes apoptosis in cancerous cells. This study aims to investigate the effects of ANXA1 on apoptosis and cell cycle arrest in K562, Jurkat and U937 cells and peripheral blood mononu-clear cells (PBMC). Cells were treated with ANXA1 and cyclophosphamide prior to flow cytometry analysis for apoptosis and cell cycle arrest induction. At 2.5µM, ANXA1 induced significant apoptosis in K562 (p ≤ 0.001) and U937 (p ≤ 0.05) cells, with EC50 values of 3.6 and 3.8 µM, respectively. In Jurkat cells, induction was not significant (EC50, 17.0 µM). No significant apoptosis induction was observed in PBMC. ANXA1 caused cycle arrest in the G0/G1 phase in K562 and U937 cells with p ≤ 0.001 for both, and (p ≤ 0.01) for Jurkat cells. ANXA1 induced apoptosis and cycle arrest in the G0/G1 phase in K562 and U937 cells, causing only cell cycle arrest in Jurkat cells.

Phosphorylation-deficient Stat1 inhibits retinoic acid–induced differentiation and cell cycle arrest in U-937 monoblasts

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2870-2878
Author(s):  
Anna Dimberg ◽  
Kenneth Nilsson ◽  
Fredrik Öberg
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Leukemic Cell ◽  
Potent Inducer ◽  
Cycle Arrest

All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of immature leukemic cell lines in vitro and of acute promyelocytic leukemia (APL) cells in vivo. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including signal transducer and activator of transcription (Stat)1. To investigate the role of Stat1 activation in ATRA signaling, sublines were established for the human monoblastic cell line U-937 constitutively expressing wild-type or phosphorylation-defective Stat1, mutated in the conserved tyrosine 701 required for dimerization and nuclear translocation. Results showed that ATRA induction leads to activation of Stat1 by the phosphorylation of tyrosine 701 and subsequent nuclear translocation. Consistent with a functional importance of this activation, ectopic expression of Stat1Y701F suppressed ATRA-induced morphologic differentiation and expression of the monocytic surface markers CD11c and the granulocyte colony-stimulating factor receptor. Moreover, ATRA-induced growth arrest in the G0/G1phase of the cell cycle was inhibited by phosphorylation-deficient Stat1. Taken together, these results indicate that Stat1 is a key mediator of ATRA-induced cell cycle arrest and differentiation of U-937 cells.

The DNA Methyltransferase Inhibitor Decitabine Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1833-1833
Author(s):  
Ken Maes ◽  
Miguel Lemaire ◽  
Jordan Gauthier ◽  
Hendrik De Raeve ◽  
Eline Menu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
Damage Response ◽  
M Phase

Abstract Abstract 1833 Multiple myeloma (MM) is still an incurable plasma cell malignancy, thus highlighting the need for alternative treatment options. Currently, strategies for therapy are being developed targeting epigenetic modification using epigenetic modulating agents like histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi). 5-aza-2'-deoxycitidine or decitabine (DAC) is a DNMTi and is FDA approved for treatment of myelodysplastic syndrome and has beneficial clinical effects against leukemia. The anti-tumor effects are ascribed to two non-mutual exclusive modes of action. Relative low doses are thought to lead to passive CpG demethylation resulting in re-expression of genes silence by DNA methylation and apoptosis, while relative high doses are cytotoxic by inducing a DNA damage response together with cell cycle arrest and apoptosis. In multiple myeloma (MM), preclinical data regarding the effects of DAC is, however, limited. Therefore, we investigated the cytotoxic effects of DAC in MM both in vitro and in vivo. In addition, we evaluated the combination of DAC with the pan-HDAC inhibitor JNJ-26481585. First, we assessed the effects of DAC on cell cycle progression and apoptosis on a panel of MM cell lines. We used one murine (5T33MMvt) and 5 human (OPM-2, RPMI 8226, LP-1, KMS-11 and NCI-H929) MM cell lines. In general, DAC could affect cell cycle progression by inducing either a G0/G1-phase arrest or a G2/M-phase arrest. The 5T33MMvt and LP-1 cells were arrested in the G2/M-phase, while OPM-2 and NCI-H929 cells underwent a G0/G1-phase arrest. Subsequently, apoptosis occurred in all cell lines. Interestingly, the 5T33MMvt cells were relatively sensitive, as nM doses of DAC were sufficient to induce massive apoptosis in a relative short incubation time (2 days). The human cell lines were less sensitive since higher doses (μM range) and longer incubation time (3–5 days) were necessary to induce apoptosis, with the OPM-2 cells being the least sensitive. To determine the potential mechanisms more in detail, we focused on the 5T33MMvt and OPM-2 cells. In both cell lines, DAC-mediated apoptosis was associated with caspase activation and PARP cleavage, Bim upregulation and posttranslational changes in Mcl-1 expression. The G2/M-phase arrest in the 5T33MMvt cells was accompanied by phosphorylation of CDK-1 and an increase in cyclinB1 expression. In both cell lines, p27 protein expression was increased, what may contribute to the cell cycle arrest. Furthermore, in the 5T33MMvt cells, a DNA damage response was activated as evidenced by a clear induction of ATM and H2AX phosphorylation. This was not the case for the OPM-2 cells, in which we observed no ATM activation and only a modest H2AX phosphorylation upon DAC treatment. In addition, the tumor suppressor p53 was phosphorylated on ser15 upon DAC treatment in both cell lines, indicating a potential role of p53. However, a p53 inhibitor, pifithrin-α, could not abrogate DAC-induced apoptosis indicating that p53 transactivation is not essential in this process. Next, we used the syngeneic 5T33 murine MM model (5T33MM) to investigate the in vivo effects of DAC. 5T33MM mice were daily treated with 0.1, 0.2 and 0.5 mg/kg DAC. We observed a significant decrease in serum M-protein, bone marrow plasmacytosis and spleno- and hepatomegaly compared to vehicle treated mice. These effects led to a significant increase in survival probability of DAC treated mice (p≤0.001). Lastly, we evaluated the possibility of combining DAC with a pan-HDAC inhibitor JNJ-26481585 (JNJ-585). DAC and JNJ-585 synergistically induced cell death in RPMI-8226, OPM-2 and 5T33MMvt cells. We further demonstrated the combinatory effects of DAC and JNJ-585 in the 5T33MM murine model. Here, we observed enhanced effects of DAC and JNJ-585 on serum M-protein, BM tumor load and survival (p≤0.001) compared to either agent alone. In conclusion, DAC shows potent anti-MM effects both in vitro and in vivo. Mechanistically, we observed induction of a DNA damage response and/or cell cycle arrest. Apoptosis was caspase-mediated but independent of the transactivation of p53. DAC was also efficient in the murine 5T33MM model in which DAC treatment led to a survival benefit. In addition, DAC showed useful in a combination with the HDAC inhibitor JNJ-585. Disclosures: No relevant conflicts of interest to declare.

A precision medicine drug discovery pipeline to identify dual CDK2/9 inhibition as a novel treatment for colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16056-e16056
Author(s):  
Roham Salman Roghani ◽  
Ali Sanjari moghaddam ◽  
Gabrielle Rupprecht ◽  
Erdem Altunel ◽  
So Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Precision Medicine ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
High Throughput ◽  
Single Agent ◽  
Cdk Inhibitor ◽  
Cycle Arrest

e16056 Background: Colorectal cancer (CRC) is the 3rdmost common form of cancer in the US, responsible for over 50,000 death each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new therapies to treat this deadly disease. To address this need, we have developed a precision medicine pipeline that integrates high throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDXs) to identify new treatments for CRC. Methods: We used high-throughput chemical screens of 2,100 compounds across five low-passage, patient-derived CRC cell lines. These results were validated using dose-response IC50curves for CDK1, CDK2, CDK9 or CDK1/2/9 inhibitors and by siRNA-mediated knockdown of CDK9 with or without CDK2 inhibition. Cell cycle arrest analysis was performed by flow cytometry and anaphase catastrophe was analyzed by immunofluorescence staining. For in vivo studies, matched PDXs were treated with either CDK2, CDK9 or dual CDK2/9 inhibitors. Results: We identified the CDK inhibitor drug class as among the most effective cytotoxic compounds across all five CRC lines. Further analysis of the CDK inhibitor class revealed that combined targeting of CDK1, 2, and 9 was the most effective, with IC50 in the range of 110 nM to 1.2 μM. We further validated the efficacy of combined CDK2/9 inhibition using siRNA-mediated knockdown of CDK9 in the presence of a CDK2 inhibitor(CVT-313), and showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Dual CDK2/9 inhibition led to significant G2/M cell cycle arrest and anaphase catastrophe. Finally, combined CDK2/9 inhibition in vivo synergistically inhibited PDX tumor growth as compared to single-agent CDK inhibitors. Conclusions: Our precision medicine pipeline revealed CDK2/9 dual inhibition as a combinatorial therapy to treat CRC and can also be used to identify new and novel therapies

Phosphorylation-deficient Stat1 inhibits retinoic acid–induced differentiation and cell cycle arrest in U-937 monoblasts

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2870-2878 ◽  
Author(s):  
Anna Dimberg ◽  
Kenneth Nilsson ◽  
Fredrik Öberg
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Leukemic Cell ◽  
Potent Inducer ◽  
Cycle Arrest

Abstract All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of immature leukemic cell lines in vitro and of acute promyelocytic leukemia (APL) cells in vivo. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including signal transducer and activator of transcription (Stat)1. To investigate the role of Stat1 activation in ATRA signaling, sublines were established for the human monoblastic cell line U-937 constitutively expressing wild-type or phosphorylation-defective Stat1, mutated in the conserved tyrosine 701 required for dimerization and nuclear translocation. Results showed that ATRA induction leads to activation of Stat1 by the phosphorylation of tyrosine 701 and subsequent nuclear translocation. Consistent with a functional importance of this activation, ectopic expression of Stat1Y701F suppressed ATRA-induced morphologic differentiation and expression of the monocytic surface markers CD11c and the granulocyte colony-stimulating factor receptor. Moreover, ATRA-induced growth arrest in the G0/G1phase of the cell cycle was inhibited by phosphorylation-deficient Stat1. Taken together, these results indicate that Stat1 is a key mediator of ATRA-induced cell cycle arrest and differentiation of U-937 cells.

scholarly journals Identification of cell cycle dependent methotrexate resistance in placenta site trophoblastic tumors

2020 ◽  
Author(s):  
Jing Xu ◽  
Ling Zhang ◽  
Qiyu Liu ◽  
Luyao Ren ◽  
Ke Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Fold Increase ◽  
Cycle Arrest ◽  
Pdx Model ◽  
Ic50 Value ◽  
Cycle Dependent

Abstract Background The purpose is to study the mechanism of chemotherapy resistance in Placental site trophoblastic tumor(PSTT).Methods We established PSTT cell lines by primary culture of a surgically resected PSTT tissues and identified the expression of immune-phenotype markers(HLA-G, β-catenin, CD146, Muc4, hPL, hCG) by immunofluorescence. We measured the IC50 value of methotrexate(MTX), etoposide(VP-16), actinomycin-D(Act-D), cisplatin(DDP), fluorouracil(5-FU) and paclitaxel(TAX) in PSTTs and used a special Mini patient-derived xenograft (Mini PDX) model to evaluate effectiveness of these drugs in vivo. Given that MTX is a cell cycle-dependent chemotherapeutic, we analyzed cell cycle characteristics of PSTT and choriocarcinoma cell lines by flow cytometry and then analyzed RNA profiles and WGS data of the PSTT cell lines to identify the potential mechanism.Results We identified the expression of HLA-G, β-catenin, CD146, hPL and hCG in PSTT cell lines. The IC50 value of MTX was 4.922 mg/ml in PSTT-1, 4.525 mg/ml in PSTT-2, 5.117 mg/ml in PSTT-3, 0.0166 µg/ml in JEG-3 cells (p༜0.001), and 0.01 µg/ml in JAR cells (p༜0.001), with nearly 50,000-fold increase in PSTTs than in choriocarcinoma, indicating that PSTTs are resistant to MTX in vitro. The Mini PDX model revealed that PSTTs are also resistant to MTX in vivo. Cell cycle analysis showed dysregulation of G1/S transition and cell cycle arrest in PSTT cell lines. RNA sequencing profile also identified cell cycle-associated genes which were differentially expressed in PSTT cells than in choriocarcinoma cell.Conclusions We found PSTTs are resistant to MTX in vitro and in vivo compared to choriocarcinoma. Mechanisms could be focused on dysregulation of the G1/S transition and cell cycle arrest.

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