Arsenic Trioxide Induces Apoptosis in Molt-4 Cell Lines: Caspase 8-Dependent and Caspase 3-Independent.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4361-4361
Author(s):  
Wenbin Qian ◽  
Wanmao Ni ◽  
Junqing Liu
Keyword(s):  
Cell Cycle ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Caspase 3 ◽  
Time Dependent ◽  
Caspase 8 ◽  
Facs Analysis ◽  
Phase Arrest ◽  
M Phase ◽  
Induction Of Apoptosis

Abstract Arsenic Trioxide (As2O3) has been used successfully in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL) without severe marrow suppression. Currently, the action of As2O3 on many other hematopoietic malignancies is under investigation. Much evidence has shown that caspase-3 plays essential executing role in apoptosis of many leukemia cell lines. But, the exact mechanism of As2O3-induced apoptosis in Molt-4 cell line which is originated from acute lymphoblastic leukemia is not well understood. Here, we investigate the action of As2O3 on Molt-4 cells and involved mechanism. Significant dose- and time-dependent inhibition of cell growth was observed by MTT assay. Following the treatment of As2O3 for 72 h, As2O3 at 4 μM exhibited 50% inhibition of growth in Molt-4 cells. The effect of As2O3 on the cell cycle was determined in Molt-4 cells by FACS analysis. DNA flow cytometric analysis with three independent experiments indicated that As2O3 induced a G1 and a G2-M phase arrest in Molt-4 cells following 6μM of exposure. Similar results were observed in Molt-4 cells following 2μM and 4μM exposure. These results indicated that As2O3 inhibited the cellular proliferation of Molt-4 cells via a G1 and a G2-M phase arrest of the cell cycle. To confirm and evaluate the induction of apoptosis, we performed the staining of cells with annexin V and PI. As with the percentages of sub-G1 group by FACS analysis, the proportion of apoptotic cells was increased in a dose-and -time dependent manner. Taken together, these results indicate that induction of apoptosis can be another mechanism of the antiproliferative effect of As2O3 besides G1 and G2-M phase arrests of the cell cycle in Molt-4 cells. We subsequently studied the activation of initiator caspase-8 and executioner caspase-3 in Molt-4 cells by Western blotting. Molt-4 cells that had undergone apoptosis on culturing with As2O3 displayed the initial activation of caspase-8 with the appearance of the large cleavage fragment of 43 to 41 kd. Despite the higher basal level of procaspase-3 expression in the Molt-4 cells prior to As2O3 treatment, we were unable to detect cleaved, activated caspase-3 following As2O3 treatment. Next, we checked whether inhibition of caspases-3 could abrogate the proapoptotic effects of As2O3. For this purpose the caspase-3 inhibitor, z-DEVD-fmk, was used. The results shown that addition of z-DEVD-fmk did not rescue Molt-4 cells from apoptosis induced by As2O3. These results clearly differ from other observations made with other leukemia cells and might explain, at least in part, that As2O3 induces apoptosis in Molt-4 cells is caspase 8-Dependent and caspase 3-Independent.

Antiproliferative and Proapoptotic Effects of Akacid-Medical-Formulation on Hematologic Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4380-4380
Author(s):  
Hannes Neuwirt ◽  
Christina Salvador ◽  
Elisabeth Wabnig ◽  
Martin Tiefenthaler ◽  
Zoran Culig ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Caspase 3 ◽  
Flow Cytometric Analysis ◽  
G1 Phase ◽  
Caspase 8 ◽  
Antiapoptotic Proteins ◽  
Phase Arrest ◽  
Downstream Effectors ◽  
Induction Of Apoptosis

Abstract We have previously shown that Akacid-medical-formulation (AMF) exerts its antiproliferative effects on various malignant solid cell lines, including those derived from prostate via downregulation of mitogen-activated protein kinases Erk 1/2 and cell cycle regulators, e.g. cdk-2, -4, cyclin E, -D1 (Neuwirt et al. 2006). However, the effect of AMF on proliferation and induction of apoptosis in malignant hematologic cell lines has not been investigated yet. Therefore, we performed 3H-thymidine incorporation assays to assess the growth inhibition of HL-60, U-937, K-562, CEM-C7H2 cells after treatment for 48 hours with various concentrations of AMF (0.3 – 100 μM). All cell lines were dose-dependently inhibited by AMF with an IC50 of about 2.1μM. As cellular growth arrest is known to be one major reason for resistance to chemotherapeutics, we investigated the effect of AMF on the cell line CEM-C7H2-6E2, in which G1/0-phase arrest can be induced by tetracyclin-regulated expression of the cell cycle inhibitor p16INK4A (Fig. 1A). Flow cytometric analysis using Annexin-V / propidium-iodide staining showed that in G1-phase arrested cells apoptosis was induced to a similar extent (LD50 of 10μM) as compared to proliferating control cells (CEM-C7H2-2C8) (Fig. 1B). In addition, we tried to find out whether AMF induces apoptosis via the caspase-9 dependent intrinsic or the caspase-8 dependent extrinsic pathway. For this purpose, two different cell lines stably transfected with tetracyclin-responsible plasmids encoding for the antiapoptotic proteins bcl-2 (CEM-C7H2-10E1) and CrmA (CEM-C7H2-2E8) were used. After 48 hours of treatment with AMF (1 – 30μM) we found that overexpression of neither bcl-2 nor CrmA could inhibit AMF-induced apoptosis compared to control cells (LD50 15μM). Data on apoptosis obtained by flow cytometry were confirmed by Western blot analysis on activated caspase-8, -9, -3, and cleaved PARP in CEM-C7H2 cells. Caspase-8 and -9 were not activated after 48 hours. However, it is interesting that downstream effectors of apoptosis, cleaved PARP and caspase-3, were strongly induced (1000 % of control at 30μM). In conclusion, our results show a potent antiproliferative effect of AMF on leukemic cell lines. Induction of apoptosis could not be inhibited either by G1-phase arrest or overexpression of the antiapoptotic proteins bcl-2 or CrmA. Although we found a substantial activation of the downstream effectors of apoptosis by AMF including caspase-3 and PARP, the upstream pathway of activation remains unclear. Figure 1 Figure 1.

Effects of Arsenic Trioxide on Megakaryocytic Cell Lines: Apoptosis, Cell Cycle Dysfunction and Signaling Pathways.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4459-4459
Author(s):  
Hubert K.B. Lam ◽  
Karen K.H. Li ◽  
Ki Wai Chik ◽  
Mo Yang ◽  
Carmen K.Y. Chuen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Annexin V ◽  
Caspase 8 ◽  
Mrna Levels ◽  
Active Caspase

Abstract Despite progress made in the elucidation of the actions of arsenic trioxide (ATO) in acute promyelocytic leukemia, the molecular mechanisms leading to apoptosis in other malignancies remain unclear. In particular, the effects of ATO on the megakaryocytic (MK) lineage have not been well characterized. In this study, we focused on two MK cell lines CHRF-288-11 (CHRF) and MEG-01, which were derived from an infant and adult acute megakaryocytic leukemia (AMKL), respectively. Our data showed that these cells underwent apoptosis within 24 – 48 h post-ATO (6 μM) treatment, as demonstrated by the Annexin V assay (Table 1). By flow cytometry, significant activation of caspase-3 was detected in the MK cells at 24 h, and was preceded by the loss of mitochondrial membrane potential (8 h) as determined by the fluorescent dye JC-1. Western blotting experiments showed that ATO induced Bax expression and down-regulated Bcl-2, which led to an increase in Bax/Bcl-2 ratio. ATO exerted immediate and significant interference on the cell cycle by delaying S-phase progression and the subsequent accumulation of cells in the G2/M phase (43.2% vs 13.6%, p < 0.01). By multivariate analysis (BrdU and 7-AAD), active caspase-3 was detected in all phases of the cell cycle. The responses of CHRF and MEG-01 cells to ATO were similar, except that the latter appeared more resistant, in terms of the dosage of ATO and the slight delayed onset of apoptosis. We screened the expression levels of 96 genes involved in apoptosis using the GEArray Q Series Human Apoptosis Gene Array at 0, 4, 8 and 16 h (each n = 2) post-ATO treatment. We identified the up-regulation of mRNA of two extrinsic components of apoptosis. Fas was progressively increased in both cell lines (up to 6.14-fold) and caspase-8 was elevated in MEG-01 (3.58-fold). The protein expressions of Fas and activated caspase-8 were demonstrated in both cell lines by flow cytometry. Increased mRNA expressions of caspase-1 (2.30-fold) and CD137 (2.33-fold) were also noted, but their significance in apoptosis of our system remained to be investigated. To demonstrate the direct effect of ATO on gene expressions in AMKL cells, a more comprehensive microarray (Human 19K Array, Ontario Cancer Institute Microarray Centre) was used. Treatment with ATO for 4 h (n = 3) prompted an elevation in the mRNA levels of stress-associated proteins, such as metallothioneins (MT1G: 6.31-fold; MT2A: 3.64-fold), Hsp72 (5.81-fold), Hsp73 (3.77-fold), Hsp90 (2.11-fold), ferritin (2.02-fold) and ubiquitin (2.76-fold). Interestingly, WT1, a cell cycle regulatory gene elevated in many types of leukemia, was induced by ATO (2.44-fold). In conclusion, our results suggested that apoptosis in AMKL cells mediated by ATO involved a switch from pro-survival in the early phase to the activation of multiple death machineries, consisting of the intrinsic (mitochondrial, Bax, Bcl-2) and the extrinsic (Fas, caspase-8) compartments. Table 1: Signals regulated by ATO in CHRF cells 0 h 24 h 48 h Mean ± SEM; * p < 0.05 compared to 0 h; # n = 2, others n = 3–5. Annexin V +/PI − (%) 4.56±0.28 8.28±0.53* 9.83±0.73* Active caspase-3 (%) 2.28±0.13 4.58±0.87* 14.7±1.16* JC-1 greenhi/redlo (%) 4.18±0.52 8.05±0.60* 20.76±8.69* Bax/Bcl-2 (Fold)# 0.63±0.08 2.65±0.68 - Fas (Fold) 1 1.73±0.17* 1.96±0.20* CD137 (Fold) 1 1.55±0.08* 1.76±0.03*

Arsenic Trioxide-Mediated Growth Inhibition of Myeloma Cells Is Associated with An Extrinsic Signaling Pathway Involved in Caspase 3 and Caspase 8.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4899-4899
Author(s):  
Jumei Shi ◽  
Yi Wu ◽  
Siqing Wang ◽  
Xiuqin Meng ◽  
Rong Wei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Arsenic Trioxide ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Caspase 3 ◽  
Myeloma Cell ◽  
Caspase 8 ◽  
Myeloma Cells

Abstract Abstract 4899 Arsenic trioxide (ATO) is a well-known inhibitor of cell proliferation in certain forms of malignancy and has been successfully used in the treatment of acute promyelocytic leukemia. Preclinical and clinical studies showed that ATO has anti-myeloma effects both as a single agent and in the combination therapy; however, the underlying molecular mechanism remains elusive. This study was performed to evaluate the molecular mechanism underlying its anti-myeloma activities. Cells from OPM2, U266, RPMI8226 myeloma cell lines and patients diagnosed with myeloma (n=6) were cultured with various concentrations of ATO for 4 days. Cell growth and viability were assayed by trypan blue dye exclusion. Cell cycle and apoptosis were analyzed by flow cytometry using CellQuest software and Vybrant Apoptosis Assay Kit. Alterations of the signaling pathways induced by ATO were tested by real-time PCR and western blot. ATO induced potent inhibition of myeloma cell growth compared with untreated control cells. Further investigation showed that ATO down-regulated c-Myc and phosphorylated (p)-Rb, while it up-regulated p53, p21Clip1, and p27Kip1 proteins, resulting in G2/M cell cycle arrest and cell growth inhibition. ATO treatment increased mRNA levels of interferon regulatory factor-1 (IRF-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as protein levels of caspase 8 and cleaved caspase 3, indicating involvement of the extrinsic apoptotic pathway. No significant change was detected in the expression levels of Bax, Bcl-xL caspase 9 and Bcl-2, indicating that the intrinsic signaling pathway was not involved. A pan-caspase inhibitor abrogated ATO-induced apoptosis of myeloma cells. Our data suggest that ATO induces apoptosis in MM cells most likely through an extracellular signaling pathway. Disclosures No relevant conflicts of interest to declare.

Arsenic trioxide–induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4078-4087 ◽  
Author(s):  
Qun Liu ◽  
Susan Hilsenbeck ◽  
Yair Gazitt
Keyword(s):  
Cell Cycle ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Myeloma Cells ◽  
Induced Apoptosis ◽  
In Cells

Abstract Arsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RARα fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G2/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G1 and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients.

scholarly journals Xylopine Induces Oxidative Stress and Causes G2/M Phase Arrest, Triggering Caspase-Mediated Apoptosis by p53-Independent Pathway in HCT116 Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Luciano de Souza Santos ◽  
Valdenizia Rodrigues Silva ◽  
Leociley Rocha Alencar Menezes ◽  
Milena Botelho Pereira Soares ◽  
Emmanoel Vilaça Costa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Cancer Cell ◽  
Caspase 3 ◽  
Cancer Cell Lines ◽  
Apoptosis Pathway ◽  
Phase Arrest ◽  
M Phase ◽  
Induced Apoptosis ◽  
Hct116 Cells

Xylopine is an aporphine alkaloid that has cytotoxic activity to cancer cells. In this study, the underlying mechanism of xylopine cytotoxicity was assessed in human colon carcinoma HCT116 cells. Xylopine displayed potent cytotoxicity in different cancer cell lines in monolayer cultures and in a 3D model of cancer multicellular spheroids formed from HCT116 cells. Typical morphology of apoptosis, cell cycle arrest in the G2/M phase, increased internucleosomal DNA fragmentation, loss of the mitochondrial transmembrane potential, and increased phosphatidylserine externalization and caspase-3 activation were observed in xylopine-treated HCT116 cells. Moreover, pretreatment with a caspase-3 inhibitor (Z-DEVD-FMK), but not with a p53 inhibitor (cyclic pifithrin-α), reduced xylopine-induced apoptosis, indicating induction of caspase-mediated apoptosis by the p53-independent pathway. Treatment with xylopine also caused an increase in the production of reactive oxygen/nitrogen species (ROS/RNS), including hydrogen peroxide and nitric oxide, but not superoxide anion, and reduced glutathione levels were decreased in xylopine-treated HCT116 cells. Application of the antioxidant N-acetylcysteine reduced the ROS levels and xylopine-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. In conclusion, xylopine has potent cytotoxicity to different cancer cell lines and is able to induce oxidative stress and G2/M phase arrest, triggering caspase-mediated apoptosis by the p53-independent pathway in HCT116 cells.

scholarly journals Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382096075
Author(s):  
Pihong Li ◽  
Luguang Liu ◽  
Xiangguo Dang ◽  
Xingsong Tian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Antitumor Effect ◽  
Caspase 3 ◽  
M Cell ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
M Phase

Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.

Biologic Sequelae of CDC2 Inhibition in MM.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4797-4797
Author(s):  
Mariateresa Fulciniti ◽  
Pierfrancesco Tassone ◽  
Teru Hideshima ◽  
Kenneth C. Anderson ◽  
Nikhil C. Munshi
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Cell Cycle Checkpoint ◽  
Time Dependent ◽  
Thymidine Uptake ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
M Phase

Abstract Multiple Myeloma (MM) is a malignant proliferation of plasma cells characterized by disruption of cell cycle checkpoint controls which maintain G2M transition and/or mitosis. CDC2 is the cyclin-dependent kinase that normally drives cells into mitosis and is universally expressed in MM. To examine the biologic role of CDC2 in MM, we evaluated cellular and molecular effects of Terameprocol (M4N, tetra-O-methyl nordihydroguaiaretic acid) that has been shown to inhibit cell cycle progression at the G2/M phase by inhibiting the transcription of sp-1 dependent expression of CDC2. We observed that Terameprocol downregulated the expression of cdc2 in a time-dependent manner, with a maximal effect at 24h. This was associated with induction of G2/M growth arrest in a panel of MM cell lines (INA6, OPM1, OPM2, MM1S, RPMI-8226, U266), as determined by PI staining. Interestingly, Terameprocol treatment led to increase in p21waf1 protein levels. Importantly, we observed inhibition of DNA synthesis by Terameprocol in a dose- and time-dependent manner, with IC50 range from 1–20 uM for a 24 hours period of treatment, as assessed by 3H-thymidine uptake. Longer exposure of MM cells to Terameprocol resulted in cytoxicity, as assessed by MTT assay, via induction of apoptosis, evidenced by Annexin V+ /PI staining, in all the MM cell lines tested. Terameprocol -induced apoptosis is predominantly associated with caspase-9 and caspase-3, but not caspase-8 activation, suggesting that Terameprocol triggers intrinsic apoptotic pathway in MM cells. Our results show that genes that control entry and progression of G2/M phase, especially cdc2, may be an attractive target for MM therapy and Terameprocol represents a prototypic agent for the control of unregulated cellular proliferation in MM.

scholarly journals The Hexane Fraction of Bursera microphylla A Gray Induces p21-Mediated Antiproliferative and Proapoptotic Effects in Human Cancer–Derived Cell Lines

2017 ◽  
Vol 16 (3) ◽  
pp. 426-435 ◽  
Author(s):  
Sabrina Adorisio ◽  
Alessandra Fierabracci ◽  
Giulia Gigliarelli ◽  
Isabella Muscari ◽  
Lorenza Cannarile ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Lines ◽  
Sonoran Desert ◽  
Caspase 3 ◽  
Human Cancer ◽  
Cell Number ◽  
Hexane Fraction ◽  
Caspase 8 ◽  
P21 Protein

Bursera microphylla (BM), one of the common elephant trees, is widely distributed in the Sonoran desert in Mexico. The Seri ethnic group in the Sonoran desert uses BM as an anti-inflammatory and painkiller drug for the treatment of sore throat, herpes labialis, abscessed tooth, and wound healing. Dried stems and leaves of BM are used in a tea to relieve painful urination and to stimulate bronchial secretion. Furthermore, BM is used for fighting venereal diseases. To investigate the effects of the hexane fraction of resin methanol extract (BM-H) on cell growth, the acute myeloid cell line (OCI-AML3) was treated with 250, 25, or 2.5 µg/mL of BM-H. The first 2 concentrations were able to significantly decrease OCI-AML3 cell number. This reduced cell number was associated with decreased S-phase, blockade of G2/M phase of the cell cycle, and increased cell death. Similar results were obtained on all tested tumor cell lines of different origins. We found that blockade of the cell cycle was a result of upregulation of p21 protein in a p53-independent way. Increase of p21 was possibly a result of upstream upregulation of p-ERK (which stabilizes p21 protein) and downregulation of p-38 (which promotes its degradation). Regarding cell death, activation of caspase-3, but not of caspase-8 or -9, was detectable after BM-H treatment. In conclusion, these data suggest that BM-H inhibited proliferation of cell lines mainly by a p21-dependent, p53-independent mechanism and promoted apoptosis through activation of caspase-3 but not caspase-8 or -9.

scholarly journals Cytotoxic Effects of Newly Synthesized Palladium(II) Complexes of Diethyldithiocarbamate on Gastrointestinal Cancer Cell Lines

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Shahram Hadizadeh ◽  
Nowruz Najafzadeh ◽  
Mohammad Mazani ◽  
Mojtaba Amani ◽  
Hassan Mansouri-Torshizi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Development Program ◽  
Water Soluble ◽  
Phase Arrest ◽  
M Phase ◽  
Ic50 Values ◽  
Pd Complexes ◽  
Hepg2 Cell Lines ◽  
Cell Cycle Status

As a part of a drug development program to discover novel therapeutic and more effective palladium (Pd) based anticancer drugs, a series of water-soluble Pd complexes have been synthesized by interaction between [Pd (phen)(H2O)2(NO3)2] and alkylenebisdithiocarbamate(al-bis-dtc) disodium salts. This study was undertaken to examine the possible cytotoxic effect of three novel complexes (0.125–64 µg/mL) on human gastric carcinoma (AGS), esophageal squamous cell carcinoma (Kyse-30), and hepatocellular carcinoma (HepG2) cell lines. The cytotoxicity was examined using cell proliferation and acridine orange/ethidium bromide (AO/EB) assay. In order to examine the effects of new Pd(II) complexes on cell cycle status, we performed cell cycle analysis. The complexes were found to have completely lethal effects on the cell lines, and the half maximal inhibitory concentration (IC50) values obtained for the cell lines were much lower in comparison with cisplatin. We demonstrated that the three new Pd(II) complexes are able to induce G2/M phase arrest in AGS and HepG2; in addition, the Pd(II) complexes caused an S phase arrest in Kyse-30 cell line. Our results indicate that newly synthesized Pd(II) complexes may provide a novel class of chemopreventive compounds for anticancer therapy.

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