Increased Mitochondrial Mass and Mitochondrial DNA Copy Number Are Biomarkers for Benzene Exposure in Hematopoietic Tissue and Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4426-4426
Author(s):  
Myung-Geun Shin ◽  
Ha-Young Eom ◽  
Hye-Ran Kim ◽  
Aerin Kwon ◽  
Dong kyun Han ◽  
...  
Keyword(s):  
Copy Number ◽  
Bone Marrow Cells ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Hematopoietic Tissue ◽  
Mtdna Copy Number ◽  
Mitochondrial Mass ◽  
Benzene Exposure ◽  
Leukemia Cell Lines

Abstract Abstract 4426 Background Exposure to benzene and its metabolites increases risk of marrow failure disorders, leukemia and other hematological diseases. However, biomarkers of benzene toxicity have not been comprehensively studied in hematopoietic cells and leukemia cells. We previously reported that benzene metabolites may impair electron chain transport and mitochondrial function (3rd WHO Conference on Children's Health and the Environment, 7-10 June 2009). Therefore, we hypothesized that alterations in mitochondrial mass and mitochondrial DNA (mtDNA) may occur in bone marrow cells and leukemia cells after benzene exposure to compensate for damaged mitochondria. Materials and Methods Total bone marrow cells from healthy individuals and leukemia cell lines (THP-1, Kasumi-1, K562, Molt-4 and HL-60) were cultured in RPMI media containing 10% fetal bovine serum for 5 days. Benzene was added in cell culture media with 0, 1 and 10mM concentration at 24 hour interval. Cell count was performed using an automated blood cell analyzer (ADVIA120, Siemens, Germany). Viability and apoptosis were assessed by tryptophan blue dye exclusion test and flowcytometry based annexin V staining protocol. Hydrogen peroxide content is measured using the commercial kit (Bioxytech® H2O2-560TM, OXIS International) according to the manufacturer's instructions. Mitochondrial mass, membrane potential and mtDNA copy number were measured using MitoTracker Green, MitoTracker Red probes (Invitrogen), and real time PCR using the QuantiTect SYBR Green PCR kit (Qiagen) and Rotor-Gene 3000 (Corbett Research), respectively. Results The number of cells were gradually increased regardless of concentration of benzene in day 3, and then steadily maintained during 3 weeks culture. Interestingly, the growth of K562 cells showed no growth inhibition effect (three fold increase) after 5-day exposure to benzene. Overall viability of five leukemia cell lines disclosed significant decrease after two week treatment of benzene (about 60% of viability was observed in 3- week suspension culture). The proportion of apoptosis was increased in time and dose dependent manner after 2-week treatment of benzene. Interestingly, mitochondrial contents and membrane potentials were dramatically increased in 3-week suspension culture after benzene exposure at dose dependent manner. The level of hydrogen peroxide significantly elevated after two week treatment of benzene (4.4 ± 1.9 μM/mg protein) compared with non-benzene treatment group (1.2 ± 1.0 μM/mg protein; P = 0.001). The average mtDNA copy number was gradually increased after exposure to benzene. Conclusions Benzene exposure caused increased mitochondrial mass and mtDNA copy number in response to oxidative stress induced by benzene. So, these mitochondrial changes can be used for biomarkers of benzene toxicity in hematopoietic tissue and leukemia cell. Disclosures: No relevant conflicts of interest to declare.

Biomarker for Benzopyrene Exposure Is Mitochondrial Mass and Mitochondrial DNA Copy in Blood Cells and Hematopoietic Tissues

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4889-4889
Author(s):  
Myung-Geun Shin ◽  
Hye-Ran Kim ◽  
Hyun-Jung Choi ◽  
Hwan-Young Kim ◽  
Dong-Kyun Han ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Mitochondrial Dna ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Copy Number ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Mtdna Copy Number ◽  
Mitochondrial Mass ◽  
Dose Dependent

Abstract Abstract 4889 Benzopyrenes are well known pollutants and carcinogens. They can intercalate into DNA and interfere transcriptions, resulting in causing various human diseases. However, biomarkers of benzopyrene toxicity have not been comprehensively studied in blood and leukemia cells. The current study was investigated to discover biomarkers for benzopyrene exposure in blood cells and leukemia cell lines. Peripheral blood, peripheral blood hematopoietic stem cell and leukemia cells (THP-1, K562, Molt-4 and HL-60) were cultured in RPMI 1640 media with adding 0, 50, 100 and 200μM of benzopyrene. Viability and apoptosis were assessed by tryptophan blue dye exclusion test and flowcytometry using annexin V. Hydrogen peroxide was measured using enzyme immunoassay. Mitochondrial mass, membrane potential and mitochondrial DNA (mtDNA) copy number were measured using MitoTracker Green, Red probes and real time PCR, respectively. The number of cell remained constant for three weeks culture. Viability of four cell lines disclosed significant decrease after two weeks of benzopyrene treatment. Apoptosis was increased in time- and dose-dependent manner after two weeks of benzopyrene treatment. Mitochondrial contents and membrane potentials were dramatically increased in three-week culture at dose dependent manner. Hydrogen peroxide level was significantly elevated after two weeks treatment of benzopyrene compared to non-benzopyrene treatment group. The number of mtDNA copy increased gradually after exposure to benzopyrene. These results indicated that increased mitochondrial mass and mtDNA copy number were biomarkers for direct exposure of benzopyrene in blood cells and hematopoietic tissues. Disclosures: No relevant conflicts of interest to declare.

The CXCR4 Antagonist AMD3100 Has Dual Effects, Initially Enhancing and Later Inhibiting Survival and Proliferation, in Myeloid Leukemia Cells in Vitro.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1721-1721
Author(s):  
Ha-Yon Kim ◽  
Ji-Young Hwang ◽  
Seong-Woo Kim ◽  
Gak-Won Yun ◽  
Young-Joon Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Leukemia Cell Lines ◽  
Number Of Cells

Abstract Abstract 1721 Poster Board I-747 AMD3100, a small bicyclam antagonist for chemokine receptor CXCR4, induces the peripheral mobilization of hematopoietic stem cells. It also induces the segregation of leukemia cells in the bone marrow microenvironment, which should enhance the chemosensitivity of the cells. Based on these observations, AMD3100 is being considered for clinical use. However, AMD3100 activates G-protein coupled with CXCR4 and acts as a partial CXCR4 agonist. In this study, we explored whether AMD3100 affects the proliferation and survival of myeloid leukemia cells. As demonstrated previously, both AMD3100 and T140, another CXCR4 antagonist, markedly inhibited stromal cell-derived factor-1 (SDF-1)-induced chemotaxis and induced the internalization of CXCR4 in myeloid leukemia cell lines (U937, HL-60, MO7e, KG1a, and K562 cells) and CD34+ primary human acute myeloid leukemia (AML) cells. SDF-1 alone did not stimulate the proliferation of these leukemia cells, nor did it rescue the cells from apoptosis induced by serum deprivation. By contrast, AMD3100, but not T140, stimulated the proliferation of all five leukemia cell lines and primary AML cells in a dose-dependent manner in serum-free conditions for up to 5 days (∼ 2-fold increases at a concentration of 10-5M), which was abrogated by pretreating the cells with pertussis toxin. AMD3100 binds to CXCR7, another SDF-1 receptor, and all of the cells examined in this study expressed CXCR4 on the cell surface to some extent. The proliferation-enhancing effects of AMD3100 were not changed by knocking-down CXCR7 using the siRNA technique, whereas knocking-down CXCR4 significantly delayed the enhanced proliferation induced by AMD3100. Neither AMD3100 nor T140 induced the phosphorylation of Akt, Stat3, MAPK p44/p42, or MAPK p38, which are involved in SDF-1 signaling. In extended cultures of these cells for up to 14 days, AMD3100, but not T140, induced a marked decrease in the number of cells, compared to the control, after incubation for 5-7 days. Adding SDF-1 at the beginning and middle of the incubation did not affect the early increase or later decrease in the number of cells. AMD3100 reduced the apoptosis of these cells to a modest degree over the first 5-7 days and then markedly increased it. Consistent with the proliferation assay, AMD3100 increased the number of leukemia cell colonies during the early period of the assay, while it markedly decreased the number and size of the colonies in the later period of the assay. In conclusion, AMD3100 exerts dual effects, initially enhancing and subsequently inhibiting the survival and proliferation, in myeloid leukemia cells in vitro. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antileukemic efficacy of 2′-deoxycoformycin in monocytic leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1512-1516
Author(s):  
Nozomi Niitsu ◽  
Yuri Yamamoto-Yamaguchi ◽  
Takashi Kasukabe ◽  
Junko Okabe-Kado ◽  
Masanori Umeda ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Combined Treatment ◽  
Single Agent ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Acute Monocytic Leukemia ◽  
U937 Cells ◽  
Monocytic Leukemia ◽  
Leukemia Cell Lines

2′-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2′-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 μmol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-β-d-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia.

scholarly journals Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells

2000 ◽  
Vol 348 (2) ◽  
pp. 425-432 ◽  
Author(s):  
Hsin-Chen LEE ◽  
Pen-Hui YIN ◽  
Ching-You LU ◽  
Chin-Wen CHI ◽  
Yau-Huei WEI
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Human Cells ◽  
Dependent Manner ◽  
Mtdna Copy Number ◽  
Human Lung Fibroblast ◽  
Mitochondrial Mass ◽  
Enhanced Production

Mitochondrial respiratory function is impaired in the target tissues of patients with mitochondrial diseases and declines with age in various human tissues. It is generally accepted that respiratory-chain defects result in enhanced production of reactive oxygen species and free radicals in mitochondria. Recently, we have demonstrated that the copy number of mitochondrial DNA (mtDNA) is increased in the lung tissues of elderly human subjects. The mtDNA copy number was suggested to be increased by a feedback mechanism that compensates for defects in mitochondria harbouring mutated mtDNA and a defective respiratory system. However, the detailed mechanism remains unclear. In this study, we treated a human lung fibroblast cell line, MRC-5, with H2O2 at concentrations of 90-360 μM. After the treatment for 24-72 h, we found that cells were arrested at G0 and G1 phases but that mitochondrial mass and mtDNA content were significantly increased in a concentration- and time-dependent manner. Moreover, the oxidative stress induced by buthionine sulphoximine was also found to cause an increase in mitochondrial mass of the treated cells. Increased uptake of a vital mitochondrial dye Rhodamine 123 and enhanced tetrazolium [MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] reduction revealed that the mitochondria increased by H2O2 treatment were functional. In addition, the increase in the mitochondrial mass was also observed in cell-cycle-arrested cells induced by mimosine, lovastatin and genistein. Taken together, these findings suggest that the increase in mitochondrial mass and mtDNA content are the early molecular events of human cells in response to endogenous or exogenous oxidative stress through cell-cycle arrest.

scholarly journals Antileukemic efficacy of 2′-deoxycoformycin in monocytic leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1512-1516 ◽  
Author(s):  
Nozomi Niitsu ◽  
Yuri Yamamoto-Yamaguchi ◽  
Takashi Kasukabe ◽  
Junko Okabe-Kado ◽  
Masanori Umeda ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Combined Treatment ◽  
Single Agent ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Acute Monocytic Leukemia ◽  
U937 Cells ◽  
Monocytic Leukemia ◽  
Leukemia Cell Lines

Abstract 2′-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2′-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 μmol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-β-d-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia.

Artesunate,a Antimalarial Agent,Exhibits Potent Anti-Leukemia Activities in Vitro and Inbibit Wnt/b-Catenin Pathway.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4822-4822
Author(s):  
Na Xu ◽  
Liu Xiaoli ◽  
Qingfeng Du ◽  
Zhi Liu ◽  
Rong Li ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
Mrna Level ◽  
Leukemia Cell ◽  
Cell Counting ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Antimalarial Agent ◽  
Leukemia Cell Lines

Abstract Abstract 4822 Artesunate (ART), a remarkable antimalarial agent, its antitumor effect was widely studied recently. But whether the antitumor mechanisms of ART involves in Wnt/b-catenin signalling, a major oncogenic pathway have yet been poorly understood. In address this question,we treated human leukemia cell lines,such as K562 cells, HL-60 cells,U937cells and KG1a cells with 12.5ug/ml,50ug/ml, 100 ug/ml and 200ug/ml ART for 24h, 48h and 72h respectively. Determined by the Cell Counting Kit-8 and flow cytometry analysis on apoptosis, we found that ART suppressed the leukemia cells proliferation and promoted the apoptosis of leukemia cells in a time- and concentration-dependent manner. Furthermore, we detected the mRNA level and protein expression of b-catenin and Wnt/b-catenin target genes c-myc and cyclinD1 by QRT-PCR and western blotting when the above leukemia cell lines treated with ART for 48h. The results demonstrated that the the mRNA level and protein expression of c-myc and cyclinD1 was lower in ART groups than in the contorl groups,and in concentration-dependent manner. on the other hand, there was no significant difference in the mRNA level and protein expression of b-catenin in the ART groups compare to the contorl groups. Moreover, we observed b-catenin by immunofluorescence technology, the Bioluminescent imaging demonstrated that ART translocated b-catenin from nucleus to adherent junctions of membrane,and binding to E-cadherin on the cell membrane. Our results provide the vitro evidence for the anti-luekemia mechanism of ART correlated to the inhibition of hyperactive Wnt/b-catenin signaling pathway. Combination With the present studies, the antitumor mechanism of ART is invoved in multiple signaling pathways, and the well known low toxicity. We thus speculate that ART might be a promising candidate drug for the treatment of leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ampelopsin Inhibits Cell Proliferation and Induces Apoptosis in HL60 and K562 Leukemia Cells by Downregulating AKT and NF-κB Signaling Pathways

2021 ◽  
Vol 22 (8) ◽  
pp. 4265
Author(s):  
Jang Mi Han ◽  
Hong Lae Kim ◽  
Hye Jin Jung
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
White Blood Cells ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Ros Generation ◽  
Anticancer Activities ◽  
Nuclear Condensation ◽  
Leukemia Cell Lines ◽  
Antileukemic Effect

Leukemia is a type of blood cancer caused by the rapid proliferation of abnormal white blood cells. Currently, several treatment options, including chemotherapy, radiation therapy, and bone marrow transplantation, are used to treat leukemia, but the morbidity and mortality rates of patients with leukemia are still high. Therefore, there is still a need to develop more selective and less toxic drugs for the effective treatment of leukemia. Ampelopsin, also known as dihydromyricetin, is a plant-derived flavonoid that possesses multiple pharmacological functions, including antibacterial, anti-inflammatory, antioxidative, antiangiogenic, and anticancer activities. However, the anticancer effect and mechanism of action of ampelopsin in leukemia remain unclear. In this study, we evaluated the antileukemic effect of ampelopsin against acute promyelocytic HL60 and chronic myelogenous K562 leukemia cells. Ampelopsin significantly inhibited the proliferation of both leukemia cell lines at concentrations that did not affect normal cell viability. Ampelopsin induced cell cycle arrest at the sub-G1 phase in HL60 cells but the S phase in K562 cells. In addition, ampelopsin regulated the expression of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors differently in each leukemia cell. Ampelopsin also induced apoptosis in both leukemia cell lines through nuclear condensation, loss of mitochondrial membrane potential, increase in reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP), and regulation of Bcl-2 family members. Furthermore, the antileukemic effect of ampelopsin was associated with the downregulation of AKT and NF-κB signaling pathways. Moreover, ampelopsin suppressed the expression levels of leukemia stemness markers, such as Oct4, Sox2, CD44, and CD133. Taken together, our findings suggest that ampelopsin may be an attractive chemotherapeutic agent against leukemia.

Aurora-A kinase: a novel target of cellular immunotherapy for leukemia

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Toshiki Ochi ◽  
Hiroshi Fujiwara ◽  
Koichiro Suemori ◽  
Taichi Azuma ◽  
Yoshihiro Yakushijin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Cellular Immunotherapy ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Hematopoietic Stem ◽  
Specific Ctls ◽  
Leukemia Cell Lines

Abstract Aurora-A kinase (Aur-A) is a member of the serine/threonine kinase family that regulates the cell division process, and has recently been implicated in tumorigenesis. In this study, we identified an antigenic 9–amino-acid epitope (Aur-A207-215: YLILEYAPL) derived from Aur-A capable of generating leukemia-reactive cytotoxic T lymphocytes (CTLs) in the context of HLA-A*0201. The synthetic peptide of this epitope appeared to be capable of binding to HLA-A*2402 as well as HLA-A*0201 molecules. Leukemia cell lines and freshly isolated leukemia cells, particularly chronic myelogenous leukemia (CML) cells, appeared to express Aur-A abundantly. Aur-A–specific CTLs were able to lyse human leukemia cell lines and freshly isolated leukemia cells, but not normal cells, in an HLA-A*0201–restricted manner. Importantly, Aur-A–specific CTLs were able to lyse CD34+ CML progenitor cells but did not show any cytotoxicity against normal CD34+ hematopoietic stem cells. The tetramer assay revealed that the Aur-A207-215 epitope–specific CTL precursors are present in peripheral blood of HLA-A*0201–positive and HLA-A*2402–positive patients with leukemia, but not in healthy individuals. Our results indicate that cellular immunotherapy targeting Aur-A is a promising strategy for treatment of leukemia.

Metabolic Profile Of Leukemia Cells Influences Treatment Efficacy Of L‑Asparaginase

2019 ◽  
Author(s):  
Katerina Hlozkova ◽  
Alena Pecinova ◽  
David Pajuelo Reguera ◽  
Marketa Simcikova ◽  
Lenka Hovorkova ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Metabolic Profile ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Lower Sensitivity ◽  
Leukemia Cell Lines

Abstract Background Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both anti-leukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs.Methods Altogether, 19 leukemia cell lines and primary leukemia cells from 11 patients were used. Glycolytic function and mitochondrial respiration were measured using Seahorse bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence.Results We characterized the basal metabolic state of the cells derived from different leukemia subtypes using cell lines and primary samples and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile, which is mainly driven by their hematopoietic lineage of origin from which they derived. However, majority of lymphoid leukemia cell lines and patients with lower sensitivity to L-asparaginase clustered regardless their hematopoietic phenotype together with myeloid leukemias. Furthermore, we observed a correlation of specific metabolic parameters with sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in other tested cytostatic drugs.Conclusions These data support the prominent role of the cell metabolism in the treatment effect of L-asparaginase. Based on these findings metabolic profile could identify leukemia patients with lower sensitivity to L-asparaginase with no specific genetic characterization.

scholarly journals Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4454
Author(s):  
Damiano Cirri ◽  
Tanja Schirmeister ◽  
Ean-Jeong Seo ◽  
Thomas Efferth ◽  
Lara Massai ◽  
...  
Keyword(s):  
Leukemia Cell ◽  
Ubiquitin Proteasome System ◽  
Multidrug Resistant ◽  
Leukemia Cells ◽  
Initial Structure ◽  
Metal Compounds ◽  
Drug Candidates ◽  
Leukemia Cell Lines ◽  
Ic50 Values ◽  
Ubiquitin Proteasome

A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

Sign in / Sign up

Export Citation Format

Share Document