Synthesis, antiproliferative and apoptosis-inducing effects of novel asiatic acid derivatives containing α-aminophosphonates

RSC Advances ◽  
2016 ◽  
Vol 6 (67) ◽  
pp. 62890-62906 ◽  
Author(s):  
Ri-Zhen Huang ◽  
Cai-Yi Wang ◽  
Jian-Fei Li ◽  
Gui-Yang Yao ◽  
Ying-Ming Pan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Agents ◽  
Mitochondrial Pathway ◽  
S Phase ◽  
Asiatic Acid ◽  
Induced Apoptosis ◽  
Dependent Pathway

Novel asiatic acid derivatives containing α-aminophosphonates was designed and synthesized as antitumor agents. Compound 3d blocked the T24 cell cycle at G1/S phase by the p53-dependent pathway and induced apoptosis through mitochondrial pathway.

scholarly journals Design, synthesis and pharmacological evaluation of new 2-oxo-quinoline derivatives containing α-aminophosphonates as potential antitumor agents

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1158-1172 ◽  
Author(s):  
Yan-Cheng Yu ◽  
Wen-Bin Kuang ◽  
Ri-Zhen Huang ◽  
Yi-Lin Fang ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hepg2 Cell ◽  
Antitumor Agents ◽  
Mitochondrial Pathway ◽  
Quinoline Derivatives ◽  
Design Synthesis ◽  
Pharmacological Evaluation ◽  
M Phase ◽  
Induced Apoptosis ◽  
Potential Antitumor

Novel 2-oxo-quinoline derivatives containing α-aminophosphonates were synthesized as antitumor agents. Compound 5b blocked HepG2 cell cycle at G2/M phase and induced apoptosis in mitochondrial pathway.

scholarly journals Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas

2005 ◽  
Vol 25 (5) ◽  
pp. 1608-1619 ◽  
Author(s):  
Hong Duan ◽  
Caroline A. Heckman ◽  
Linda M. Boxer
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Chromatin Immunoprecipitation ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Transcriptional Level ◽  
Cycle Arrest ◽  
Induced Apoptosis

ABSTRACT Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPα and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPα binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.

scholarly journals Sophoridine induces apoptosis and S phase arrest via ROS-dependent JNK and ERK activation in human pancreatic cancer cells

2017 ◽  
Vol 36 (1) ◽  
Author(s):  
Zihang Xu ◽  
Fei Zhang ◽  
Chao Bai ◽  
Chao Yao ◽  
Hairong Zhong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Agents ◽  
S Phase ◽  
Human Pancreatic Cancer ◽  
Drug Candidate ◽  
Western Blot Assay ◽  
Pancreatic Cancer Cells

Abstract Background Pancreatic cancer is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Novel, selective antitumor agents are pressingly needed. Methods CCK-8 and colony formation assay were used to investigate the cell growth. Flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. The peroxide-sensitive fluorescent probe DCFH-DA was used to measure the intracellular ROS levels. Western blot assay was used to detect the levels of cell cycle and apoptosis related proteins. Xenografts in nude mice were used to evaluate the effect of Sophoridine on pancreatic cancer cell in vivo. Results Sophoridine killed cancer cells but had low cytotoxicity to normal cells. Pancreatic cancer cells were particularly sensitive. Sophoridine inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest at S phase and mitochondrial-related apoptosis. Moreover, Sophoridine induced a sustained activation of the phosphorylation of ERK and JNK. In addition, Sophoridine provoked the generation of reactive oxygen species (ROS) in pancreatic cancer cells. Finally, in vivo, Sophoridine suppressed tumor growth in mouse xenograft models. Conclusion These findings suggest Sophoridine is promising to be a novel, potent and selective antitumor drug candidate for pancreatic cancer.

Paris Saponin VII Induces Apoptosis and Cell Cycle Arrest in Erythroleukemia Cells by a Mitochondrial Membrane Signaling Pathway

2020 ◽  
Vol 20 ◽  
Author(s):  
Xin Lin ◽  
Babu Gajendran ◽  
Krishnapriya M. Varier ◽  
Wuling Liu ◽  
Jingrui Song ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Mtt Assay ◽  
Mitochondrial Membrane ◽  
Antimicrobial Activities ◽  
Mitochondrial Pathway ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Hel Cells

Background and Purpose: Leukemia considered a top-listed ailment, according to WHO, which contributes to the death of a major population of the world every year. Paris Saponin VII (PS), a saponin which was isolated from the roots of Trillium kamtschaticum, from our group, was reported to provide hemostatic, cytotoxic and antimicrobial activities. However, its molecular mechanism underlying the anti-proliferative effects remains unclear. Thus, this study hypothesized to assess that mechanism in PS treated HEL cells. Methods: The MTT assay used to analyze the PS inhibited cell viability in the HEL cells. We further found that PS could induce S phase cell cycle arrest through flow cytometry as well as the western blot analysis of intrinsic and extrinsic apoptotic molecules. Results: The MTT assay showed the IC50 concentration of PS as 0.667μM. The study revealed that PS treatment inhibits cell proliferation dose-dependently. It further caused mitochondrial membrane potential changes by PS treatment. Mechanistic protein expression revealed a dose-dependent upsurge for Bid and Bim molecules, while Bcl2 and PARP expression levels were significantly (P< 0.05) down-regulated in PS treated HEL cells resulting in caspase -3 release and increased the Bim levels upon 24h of incubation. Conclusions: These findings indicate that PS possesses an excellent anti-leukemic activity via regulation of the mitochondrial pathway, leading to S phase cell cycle arrest and caspase-dependent apoptosis suggesting it as a potential alternative chemotherapeutic agent for leukemia patients.

Topotecan Induces -Apoptosis in the Myelodysplastic Syndromes Cell Line MUTZ-1 That Is Associated with down Regulation of IAP Expression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4713-4713
Author(s):  
Zhen Cai ◽  
Wenjun Wu Master
Keyword(s):  
Cell Cycle ◽  
Myelodysplastic Syndromes ◽  
S Phase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Dna Ladder ◽  
Down Regulation ◽  
Transmission Electron ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract Myelodysplastic syndromes (MDS) represent a heterogenous group of clonal stem cell disorders with qualitative and quantitative abnormalities of blood cells and a high probability of evolving to acute leukemia. Intensive induction chemotherapy in order to reduce the malignant clone and reconstruct normal hematopoiesis is a classic therapy of MDS, especially high risk MDS. Topotecan (TPT), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I and has been extensively studied in hematologic malignances. However, little is known about how TPT acts against neoplastic cells. The aim of this study is to evaluate apoptotic effect of TPT on the MDS cell line MUTZ-1 and its associated changes in the expression of inhibitors of apoptosis protein (IAPs). The effect of TPT on MUTZ-1 growth was determined by using MTT assay. Characteristics associated with apoptosis induced by TPT were evaluated by transmission electron microscope, DNA gel electrophoresis and flow cytometry (FCM). Cell cycle shift were observed by FCM. Semi-quantitative RT-PCR was used to evaluate the mRNA expression of members of IAP gene family, including survivin, XIAP, Bcl-2, Bax, cIAP1 andcIAP2. The potential of mitochondrial membrane potential (MMP) was determined by using JC-1 probe. The results demonstrated that TPT significantly inhibited MUTZ-1 cell growth in a time- and dose-dependent manner with IC50 of 5.011 mmol/L, 1.297mmol/L and 0.483mmol/L at 24h, 48h and 72h respectively. Morphological features associated with TPT-induced apoptosis observed by transmission electron microscopy included cytoplasmic and nuclear shrinkage, karyorrhexis, nuclear convolution, chromatin condensation and margination, cytoplasmic vacuolization, and membrane-bound apoptotic bodies. An ambiguous DNA ladder was observed following treatment with 5mmol/L TPT for 24h, and a typical DNA ladder was observed with 10mmol/L TPT for 24h. The apoptotic rates were 11.69±0.51%, 34.07±1.73%, and 48.59±2.01%, respectively, after 24h culture with TPT as 1, 5, 10 μmol/L, significantly higher than that of the control (3.47%±0.3%; F=31.642, P<0.01). The percentage of MUTZ-1 cells in G2/M phase of the cell cycle decreased while in S and G0/G1 phase increased after treatment with 1mmol/L TPT for 24h,. The majority of the cells were arrested in S phase. After 24h culture with TPT at1, 5, and 10μmol/L, the mRNA levels of survivin, XIAP, cIAP1 and cIAP2 were decreased (P<0.01). This down-regulation was negatively correlated with TPT-induced apoptotic rates(P<0.05). There was no significant change in the Bax and Bcl-2 mRNA levels after TPT treatment (P>0.05). After 24h culture with 1μmol/L TPT, the MMP of TPT treated cells decreased significantly(P<0.01). Together, we conclude TPT can inhibit the growth and induce apoptosis of MUTZ-1 cells in a time- and dose- dependent manner. TPT can also induce the cell cycle changes, with the majoritoy of cells being arrested in S phase. The TPT-induced apoptosis in MUTZ-1 cells is associated with down-regulation of suvivin, XIAP, cIAP1and cIAP2 mRNA expresison. As well, MMP may be play a important role in the apoptotic process of MUTZ-1 cells induced by TPT.

scholarly journals The susceptibility of granulosa cells to apoptosis is influenced by oestradiol and the cell cycle

2006 ◽  
Vol 189 (3) ◽  
pp. 441-453 ◽  
Author(s):  
Susan M Quirk ◽  
Robert G Cowan ◽  
Rebecca M Harman
Keyword(s):  
Cell Cycle ◽  
Granulosa Cells ◽  
Cell Cycle Progression ◽  
Fas Ligand ◽  
S Phase ◽  
G1 Phase ◽  
Cycle Progression ◽  
Induced Apoptosis ◽  
Cell Proliferation Marker ◽  
D2 Protein

Experiments were conducted to test whether oestradiol (E2) protects granulosa cells from Fas ligand (FasL)-induced apoptosis and whether protection involves modulation of the cell cycle of proliferation. Treatment of cultured bovine granulosa cells with E2 decreased susceptibility to FasL-induced apoptosis. The effects of E2 were mediated through oestrogen receptor and were not mediated by stimulation of IGF production. E2 also increased the percentage of cells progressing from G1 to S phase of the cell cycle, and increased expression of cyclin D2 protein and the cell proliferation marker Ki67. Progression from G1 to S phase of the cell cycle was necessary for the protective effect of E2; blocking progression from G1 to S phase with the cdk2 inhibitor roscovitine, or blocking cells in S phase with hydroxyurea, prevented protection by E2. The stages of the cell cycle during which granulosa cells are susceptible to apoptosis were assessed. First, treatment with the G1 phase blocker, mimosine, protected cells from FasL-induced apoptosis, indicating that cells in G0 or early- to mid-G1 phase are relatively resistant to apoptosis. Secondly, examination of recent DNA synthesis by cells that became apoptotic indicated that apoptosis did not occur in S, G2 or M phases. Taken together, the experiments indicate that cells may be most susceptible to apoptosis at the transition from G1 to S phase. E2 stimulates transition from G1 to S phase and protects against apoptosis only when cell cycle progression is unperturbed.

scholarly journals Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3096-3106 ◽  
Author(s):  
Ramesh Balusu ◽  
Warren Fiskus ◽  
Rekha Rao ◽  
Daniel G. Chong ◽  
Srilatha Nalluri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Chaperone ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
S Phase ◽  
Wild Type ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Induced Apoptosis ◽  
Export Signal

Abstract Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1 induced p53 and p21, decreased the percentage of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and unmutated NPM1. Notably, knockdown of NPM1 by shRNA abolished lethal AML phenotype induced by OCI-AML3 cells in NOD/SCID mice. Knockdown of NPM1 also sensitized OCI-AML3 to all-trans retinoic acid (ATRA) and cytarabine. Inhibition of NPM1 oligomerization by NSC348884 induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+ to ATRA. This effect was significantly less in AML cells coexpressing FLT3-ITD, or in AML or normal CD34+ progenitor cells expressing wild-type NPM1. Thus, attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes NPM1c+ expressing AML cells to treatment with ATRA and cytarabine.

Temporal and spatial expression of the cell-cycle regulator cul-1 in Drosophila and its stimulation by radiation-induced apoptosis

2000 ◽  
Vol 203 (18) ◽  
pp. 2747-2756 ◽  
Author(s):  
V. Filippov ◽  
M. Filippova ◽  
F. Sehnal ◽  
S.S. Gill
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Cultured Cells ◽  
Lethal Dose ◽  
S Phase ◽  
Model Organisms ◽  
Cell Cycle Regulators ◽  
Protein Levels ◽  
Pass Through ◽  
Induced Apoptosis

Cul-1 protein is part of the ubiquitin ligase complex that is conserved from yeast to humans. This complex specifically marks cell-cycle regulators for their subsequent destruction. Two null mutations of the cul-1 gene are known, in budding yeast and in nematodes. Although in both these organisms the cul-1 gene executes essentially the same function, the manifestation of its lack-of-function mutations differs considerably. In yeast the mutation causes arrest at the G(1)/S-phase transition, whereas in nematodes excessive cell divisions occur because mutant cells are unable to exit the mitotic cycle. We isolated cul-1 orthologues from two model organisms, Drosophila melanogaster and mouse. We show that the Drosophila full-length cul-1 gene restores the yeast mutant's inability to pass through the G(1)/S-phase transition. We also characterize expression of this gene at the transcript and protein levels during Drosophila development and show that cul-1 gene is maternally supplied as a protein, but not as an RNA transcript. Zygotic transcription of the gene, however, resumes at early stages of embryogenesis. We also found an increase in cul-1 transcription in cultured cells treated with a lethal dose of gamma-irradiation.

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