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1.
Mol Biol Rep ; 51(1): 201, 2024 Jan 25.
Article in English | MEDLINE | ID: mdl-38270665

ABSTRACT

BACKGROUND: Pyroptosis is an inflammatory type of programmed cell death, and could overcome the drug-resistance induced by anti-apoptotic effect of cancers. Carvedilol (CVL), a ß-adrenergic receptors antagonist, has shown anti-inflammatory response and anti-cancer effect. The aim of this study is to investigate whether pyroptosis can be activated by CVL in prostate cancer (PCa). METHODS AND RESULTS: Datasets were used to analyze the expressions of pyroptosis-related proteins. Intracellular morphological change, cell viability, LDH and Il-1ß release by cells,, and Hoechst/PI staining were used to detect the occurrence of pyroptosis. Realtime-PCR, western blot, immunofluorescence, and immunohistochemistry (IHC) were used to investigate the expressions of pyroptosis-related proteins. Datasets analyze showed the expressions of NLRP3, Caspase 1, ASC and GSDMD were all decreased in PCa comparing with normal tissues, but without prognostic significance. CVL treatment weakened the viabilities of PCa cells. Cell morphology changing, cytoplasmic vacuole formation, membrane integrity loss, LDH and IL-1ß release and PI positive cells increasing were observed. NLRP3, Caspase 1, ASC, GSDMD and N-GSDMD expressions were elevated after CVL treatment, accompanied by a tendency of NF-κB transferring into nucleus. In vivo, CVL inhibited the growth of subcutaneous transplanted tumor. IHC showed CVL increased the expressions of NLRP3, ASC, and GSDMD, and decreased the expression of Ki-67 in transplanted tumor tissues. CONCLUSION: This study demonstrated that CVL could induce pyroptosis in PCa cells through NLRP3-caspase1-ASC inflammasome by promoting nuclear translocation of NF-κB, which would lay a foundation for the application of adrenergic receptor antagonist in PCa.


Subject(s)
NF-kappa B , Prostatic Neoplasms , Male , Humans , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Carvedilol , Pyroptosis , Caspase 1 , Prostatic Neoplasms/drug therapy
2.
Pharmacol Res ; 175: 106040, 2022 01.
Article in English | MEDLINE | ID: mdl-34954029

ABSTRACT

Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.


Subject(s)
Forkhead Box Protein M1/antagonists & inhibitors , Pancreatic Neoplasms/drug therapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Pyridines/therapeutic use , Thiophenes/therapeutic use , Animals , Apoptosis/drug effects , BRCA1 Protein/genetics , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Comet Assay , Female , Forkhead Box Protein M1/genetics , Forkhead Box Protein M1/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice, Inbred BALB C , Mice, Nude , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/genetics , Pyridines/pharmacology , Signal Transduction/drug effects , Thiophenes/pharmacology , cdc25 Phosphatases/genetics
3.
Phytomedicine ; 124: 155288, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38183698

ABSTRACT

BACKGROUND: The scarcity of drugs targeting AML cells poses a significant challenge in AML management. Z-Ligustilide (Z-LIG), a phthalide compound, shows promising pharmacological potential as a candidate for AML therapy. However, its precise selective mechanism remains unclear. PURPOSE: In order to assess the selective inducement effects of Z-LIG on ferroptosis in AML cells and explore the possible involvement of the Nrf2/HO-1 pathway in the regulation of ferroptosis. METHODS: Through in vitro cell proliferation and in vivo tumor growth tests, the evaluation of Z-LIG's anticancer activity was conducted. Ferroptosis was determined by the measurement of ROS and lipid peroxide levels using flow cytometry, as well as the observation of mitochondrial morphology. To analyze the iron-related factors, western blot analysis was employed. The up-regulation of the Nrf2/HO-1 axis was confirmed through various experimental techniques, including CRISPR/Cas9 gene knockout, fluorescent probe staining, and flow cytometry. The efficacy of Z-LIG in inducing ferroptosis was further validated in a xenograft nude mouse model. RESULTS: Our study revealed that Z-LIG specifically triggered lipid peroxidation-driven cell death in AML cells. Z-LIG downregulated the total protein and nuclear entrance levels of IRP2, resulting in upregulation of FTH1 and downregulation of TFR1. Z-LIG significantly increased the susceptibility to ferroptosis by upregulating ACSL4 levels and simultaneously suppressing the activity of GPX4. Notably, the Nrf2/HO-1 pathway displayed a twofold impact in the ferroptosis induced by Z-LIG. Mild activation suppressed ferroptosis, while excessive activation promoted it, mainly driven by ROS-induced labile iron pool (LIP) accumulation in AML cells, which was not observed in normal human cells. Additionally, Nrf2 knockout and HO-1 knockdown reversed iron imbalance and mitochondrial damage induced by Z-LIG in HL-60 cells. Z-LIG effectively inhibited the growth of AML xenografts in mice, and Nrf2 knockout partially weakened its antitumor effect by inhibiting ferroptosis. CONCLUSION: Our study presents biological proof indicating that the selective initiation of ferroptosis in leukemia cells is credited to the excessive activation of the Nrf2/HO-1 pathway triggered by Z-LIG.


Subject(s)
4-Butyrolactone/analogs & derivatives , Ferroptosis , Leukemia, Myeloid, Acute , Humans , Mice , Animals , Reactive Oxygen Species/metabolism , NF-E2-Related Factor 2/metabolism , Leukemia, Myeloid, Acute/metabolism , Iron/metabolism
4.
BMC Med Genet ; 13: 19, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-22436304

ABSTRACT

BACKGROUND: Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the NF2 gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient. CASE PRESENTATION: We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing NF2, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1).Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1, PITPNB and TTC28. MN1, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (TEL/MN1) in human myeloid leukemias. Interestingly, Mn1-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22, a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. CONCLUSIONS: Thus, our report describes a NF2-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 22/genetics , Cleft Palate/complications , Maxillofacial Development/genetics , Neurofibromatosis 2/complications , Pierre Robin Syndrome/complications , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Animals , Base Pairing/genetics , Child , Child, Preschool , Cleft Palate/genetics , Facies , Female , Humans , Infant , Infant, Newborn , Mice , Neurofibromatosis 2/genetics , Pierre Robin Syndrome/genetics , Pregnancy , Skull/abnormalities , Skull/pathology , Trans-Activators
5.
Eur J Med Chem ; 230: 114116, 2022 Feb 15.
Article in English | MEDLINE | ID: mdl-35091172

ABSTRACT

Inducing the deficiency of homologous recombination (HR) repair is an effective strategy to broaden the indication of PARP inhibitors in pancreatic cancer treatment. Repression of BRD4 has been reported to significantly elevate HR deficiency and sensitize cancer cells to PARP1/2 inhibitors. Inspired by the concept of synthetic lethality, we designed, synthetized and optimized a dual PARP1/BRD4 inhibitor III-7, with a completely new structure and high selectivity against both targets. III-7 repressed the expression and activity of PARP1 and BRD4 to synergistically inhibit the malignant growth of pancreatic cancer cells in vitro and in vivo. Based on the results of bioinformatic analysis, we found that Olaparib induced the acceleration of mitosis and recovery of DNA repair to cause the generation of drug resistance. III-7 reversed Olaparib-induced adaptive resistance and induced cell cycle arrest and DNA damage by perturbing PARP1 and BRD4-involved signaling pathways. We believe that the PARP1/BRD4 dual inhibitors are novel and promising antitumor agents, which provide an efficient strategy for pancreatic cancer treatment.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Pancreatic Neoplasms , Transcription Factors/antagonists & inhibitors , Cell Line, Tumor , Humans , Pancreatic Neoplasms/drug therapy , Phthalazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
6.
Cell Death Dis ; 12(12): 1138, 2021 12 08.
Article in English | MEDLINE | ID: mdl-34880209

ABSTRACT

Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.


Subject(s)
Pyridines/pharmacokinetics , Thiophenes/pharmacokinetics , Triple Negative Breast Neoplasms , Cell Cycle/genetics , Cell Division , Cell Line, Tumor , DNA Damage , Forkhead Box Protein M1/genetics , Humans , Phthalazines/pharmacology , Phthalazines/therapeutic use , Piperazines , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism
7.
J Med Chem ; 64(23): 17413-17435, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34813314

ABSTRACT

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Cell Cycle Proteins/antagonists & inhibitors , Drug Discovery , Pancreatic Neoplasms/drug therapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Transcription Factors/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Autophagy/drug effects , DNA Damage , DNA Repair , Gene Expression Regulation, Neoplastic/drug effects , Genes, BRCA1 , Humans , Pancreatic Neoplasms/pathology , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Rad51 Recombinase/genetics
8.
Pediatr Blood Cancer ; 52(1): 139-42, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18819128

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disorder of infancy and childhood that is invariably fatal if not treated. We report on the first patient to receive post-natal HSCT for HLH after receiving in utero chemotherapy for disease stabilization.


Subject(s)
Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/therapy , Antineoplastic Agents/therapeutic use , Cognition Disorders , Developmental Disabilities , Female , Fetal Therapies , Fetus , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Infant, Newborn , Lymphohistiocytosis, Hemophagocytic/physiopathology , Pregnancy
9.
Cancer Genet Cytogenet ; 136(2): 138-40, 2002 Jul 15.
Article in English | MEDLINE | ID: mdl-12237238

ABSTRACT

We report a case of transient myeloproliferative disorder (TMD) that occurred in a phenotypically normal infant with low level constitutional mosaicism of i(21q). To the best of our knowledge, this is the first documented case of TMD with constitutional i(21q) mosaicism.


Subject(s)
Chromosomes, Human, Pair 21 , Isochromosomes , Mosaicism , Myeloproliferative Disorders/genetics , Humans , Infant, Newborn , Male
10.
Cancer Genet Cytogenet ; 144(2): 106-11, 2003 Jul 15.
Article in English | MEDLINE | ID: mdl-12850372

ABSTRACT

The purpose of this study was to evaluate stable DNA transfection of M-21 human melanoma cells with particle-mediated gene transfer (PMGT) with B7-1 cDNA and to identify sites of gene integration. Stable B7-1 transfectants (M-21-B7) were obtained with PMGT using a plasmid vector containing cDNA for both B7-1 and neomycin phosphotransferase, with subsequent selection with G418. The transfected cells were flow sorted by B7-1 expression into two populations, bright and dim. The bright population had 85%-90% of cells expressing B7-1; the dim population had less than 50% of cells with B7-1 expression. Chromosome analysis with fluorescence in situ hybridization (FISH) and G-banding showed that 70% of bright cells had two main integration sites, with extensive amplification of the transgene. The dim population had random signal distribution, with little or no amplification, despite G418 selection. Because B7-1 has been mapped to 3q21, FISH was performed using a chromosome 3 painting probe (WCP) together with a probe for B7-1. In transfected bright M-21 cells, amplified genes that hybridized with the B7-1 construct were localized to chromosome 3 material inserted into marker chromosomes. These data suggest that B7-1 insertion may involve homologous recombination, but maintenance of integration and amplification required selection.


Subject(s)
B7-1 Antigen/genetics , DNA/analysis , Gene Transfer, Horizontal , Melanoma/genetics , Humans , In Situ Hybridization, Fluorescence , Plasmids , Transfection , Transgenes , Tumor Cells, Cultured
12.
Pediatr Dev Pathol ; 10(3): 229-32, 2007.
Article in English | MEDLINE | ID: mdl-17535087

ABSTRACT

We report a case of a 12-month-old girl with stage 3 neuroblastoma composed of 2 distinct clones in the adrenal primary tumor. One clone showed neuroblastoma, poorly differentiated subtype with a low mitosis-karyorrhexis index (favorable histology), and the other was neuroblastoma, poorly differentiated subtype with a high mitosis-karyorrhexis index (unfavorable histology), according to the International Neuroblastoma Pathology Classification. Fluorescent-labeled in-situ hybridization using the formalin-fixed, paraffin-embedded material showed that the MYCN oncogene was amplified in the latter clone but not in the former clone. Lymph nodes from ipsilateral and contralateral sides contained metastatic neuroblastoma of the latter clone. It is well documented that tumors in the Ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor) category are composite and composed of multiple clones. To our knowledge, however, this is the 1st case report of composite tumor with biologically favorable and unfavorable clones in the Neuroblastoma (Schwannian stroma-poor) category.


Subject(s)
Adrenal Gland Neoplasms/pathology , Neuroblastoma/pathology , Adrenal Gland Neoplasms/diagnostic imaging , Adrenal Gland Neoplasms/surgery , Clone Cells , Female , Ferritins/blood , Homovanillic Acid/urine , Humans , In Situ Hybridization, Fluorescence , Infant , L-Lactate Dehydrogenase/blood , N-Myc Proto-Oncogene Protein , Neoplasm Staging , Neuroblastoma/classification , Neuroblastoma/diagnostic imaging , Neuroblastoma/surgery , Nuclear Proteins/metabolism , Oncogene Proteins/metabolism , Radiography , Treatment Outcome , Vanilmandelic Acid/urine
13.
Blood ; 109(2): 503-6, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-16973956

ABSTRACT

A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.


Subject(s)
Adenosine Deaminase/deficiency , Chromosomes, Human, Pair 8/genetics , Genetic Therapy , Mosaicism , Pancytopenia/therapy , Severe Combined Immunodeficiency/therapy , Trisomy , Adenosine Deaminase/genetics , Child, Preschool , Cytogenetic Analysis , Female , Humans , Pancytopenia/etiology , Retrospective Studies , Severe Combined Immunodeficiency/genetics
14.
J Pediatr Hematol Oncol ; 25(7): 520-5, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12847317

ABSTRACT

At diagnosis, clonal chromosomal abnormalities are found in the bone marrow blasts in more than two thirds of children with acute lymphoblastic leukemia (ALL). Practically, however, failure to detect these abnormalities is frequent and usually attributed to poor marrow sampling, inadequate metaphases, and/or a preponderant mitotic activity among nonleukemic cells. The authors applied fluorescence in situ hybridization (FISH) techniques to re-examine 30 cases of karyotypically "normal" childhood ALL to explore the role of preponderant mitotic activities of nonleukemic cells in failures to detect clonal abnormalities. The FISH test were performed using TEL/AML1 fusion gene probe and the centromere probes for chromosome 8 and 10 to detect the t(12;21) translocation and/or hyperdiploidy. Half of the karyotypically "normal" ALL cases examined have been found to have abnormal clones with t(12;21) rearrangement and/or hyperdiploidy by this specially designed FISH assay. Contrary to expectation, the authors found a higher incidence (52%) of clonal abnormalities in cases where over 20 metaphases had been examined than in cases (44%) where fewer than 20 metaphases had been analyzed. These findings suggest that a preponderant mitotic activity of nonleukemic cells plays an important role in failures to detect an abnormal clone by conventional cytogenetic studies. Therefore, karyotypically "normal" childhood ALL patients should undergo FISH studies to rule out the presence of t(12;21) and/or hyperdiploid clone.


Subject(s)
Bone Marrow Cells/pathology , Chromosome Aberrations , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adolescent , Antigens, CD/blood , Blast Crisis/pathology , Child , Child, Preschool , Chromosome Banding , Female , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Karyotyping , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
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