Cyclin D1 expression in acute leukemia

Aref, Salah; Mabed, Mohamed; El‐Sherbiny, M.; Selim, Tarek; Metwaly, A.

doi:10.1080/10245330500322321

Cited by 20 publications

(22 citation statements)

References 9 publications

(8 reference statements)

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“…In agreement with previous studies, [13,[19][20][21], we found over expression of cyclin D1 and Ki-67 in ALL patients. On the other hand, [22] we did not detect any elevation of cyclin D1 level among their ALL patient group (0/24).…”

Section: Discussionsupporting

confidence: 82%

“…In accordance with previous results, [19][20][21]25], the frequency of cell cycle parameters (Ki-67 and cyclin D1)- positive ALL was higher in patients presenting with organomegaly and lymphadenopathy although not statistically significant. Cyclin D1 overexpression might have a role in blast mobilization from the bone marrow to lymph nodes [21] and Ki-67 expression was also related to organomegaly and extramedullary infiltration in ANLL with some reports concerning specific organ infiltrates [20,26].…”

Section: Discussionsupporting

confidence: 80%

“…Cyclin D1 overexpression might have a role in blast mobilization from the bone marrow to lymph nodes [21] and Ki-67 expression was also related to organomegaly and extramedullary infiltration in ANLL with some reports concerning specific organ infiltrates [20,26]. CR complete remission, IPT immunophenotyping, Hb hemoglobin, TLC total leucocytic count, PLT platelet count The aim of this study was to correlate PGP expression with cell cycle parameters expression, however, we could not draw a firm conclusion if PGP positive cells are cycling or not cycling because of the small number (ten patients) of PGP positive patients.…”

Section: Discussionmentioning

confidence: 99%

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Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

El-Sayed

Ismail

Moneer

2011

Indian J Hematol Blood Transfus

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Previous studies showed that non-cycling cells have a higher multidrug resistance (MDR) expression, which may be down-regulated by proliferation induction. Triggering these cells into proliferation down-regulates high MDR expression. The aim of this study was to determine the expression of P-glycoprotein (PGP) and cell cycle parameters (cyclin D1 and Ki-67) in acute lymphoblastic leukemia (ALL) at diagnosis, and to evaluate the correlation between the expressions of each marker, and the clinical significance of such expression with response to induction chemotherapy and overall survival. A total of 78 newly diagnosed ALL patients were enrolled in our study. PGP, cyclin D1 and Ki-67 were determined by flow cytometry. PGP expression was encountered in 10/78 (12.8%) of ALL cases. Cyclin D1 and Ki-67 were expressed in 16/77 (20.6%) and 27/76 (34.6%) of ALL cases, respectively. None of the parameters were associated with response to induction chemotherapy and overall survival. Based on the current analysis, we conclude that a joint immunophenotypic evaluation of PGP and cell cycle parameters like that adopted in this study is unlikely to reveal mechanisms of multidrug resistance associated with the clinical outcome.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

El-Sayed

Ismail

Moneer

2011

Indian J Hematol Blood Transfus

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“…In the current study, we showed that 1 to 5 M doses of ZnPP suppress cell proliferation in K562 and HepG2 cells in part by inhibiting cyclin D1 expression. Corroborating our findings, the overexpression of cyclin D1 is known to play a role in hepatoma and leukemia development by stimulating cell proliferation (35,36). Additionally, we showed that ZnPP significantly inhibited the expression of a number of genes critically related to cell proliferation and angiogenesis ( Table 1).…”

Section: Discussionmentioning

confidence: 64%

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and upregulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis. Zinc protoporphyrin IX (ZnPP)2 is a metabolite formed in trace amounts during heme biosynthesis. In this process, the final reaction is the chelation of zinc in the protoporphyrin ring, whereas heme is formed by chelation of iron in the ring. During periods of iron insufficiency or impaired iron utilization, ZnPP formation is enhanced. Clinically, ZnPP quantification is a sensitive and specific tool for measuring iron mineral status and metabolism (1). In addition, ZnPP regulates heme catabolism through competitively inhibiting the activity of heme oxygenase (HO), the rate-limiting enzyme in the heme degradation pathway that produces carbon monoxide and biliverdin. The latter is rapidly reduced to bilirubin by biliverdin reductase. Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3-6).Whereas ZnPP has been largely studied in relation to its inhibition of HO activity, reports show that ZnPP could exert cellular effects independent of HO activity (7,8). In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11). Although the underling mechanism is unknown, zinc mesoporphyrin, another analogue of heme, has been shown to induce HMOX1 expression by accelerating Bach1 protein degradation (12). Heme itself can affect gene expression by associating with transcription factors (13,14). Th...

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“…In ALL, alterations in Cyclins D1 -CCND1 [5], [6], D3 -CCND3 [7], E1 -CCNE1 [8] and A1-CCNA1 [9], Cyclin dependent kinases (CDK) 2 &6 -CDK2 & CDK6 [10], [11] [Figure 1], cyclin dependent kinase inhibitors CDKN2A, CDKN2B [12], CDKN1B [13], CDKN1C [14] have been reported. The differential expression, especially of the cyclins and the CDKs, leads to loss of checkpoint control and hence results in neoplastic transformation, which is also evident from our earlier studies [15]–[17] and hence these proteins would serve as important drug targets.…”

Section: Introductionmentioning

confidence: 99%

Drug Targets for Cell Cycle Dysregulators in Leukemogenesis: In Silico Docking Studies

Jayaraman¹,

Jamil²

2014

PLoS ONE

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Alterations in cell cycle regulating proteins are a key characteristic in neoplastic proliferation of lymphoblast cells in patients with Acute Lymphoblastic Leukemia (ALL). The aim of our study was to investigate whether the routinely administered ALL chemotherapeutic agents would be able to bind and inhibit the key deregulated cell cycle proteins such as - Cyclins E1, D1, D3, A1 and Cyclin Dependent Kinases (CDK) 2 and 6. We used Schrödinger Glide docking protocol to dock the chemotherapeutic drugs such as Doxorubicin and Daunorubicin and others which are not very common including Clofarabine, Nelarabine and Flavopiridol, to the crystal structures of these proteins. We observed that the drugs were able to bind and interact with cyclins E1 and A1 and CDKs 2 and 6 while their docking to cyclins D1 and D3 were not successful. This binding proved favorable to interact with the G1/S cell cycle phase proteins that were examined in this study and may lead to the interruption of the growth of leukemic cells. Our observations therefore suggest that these drugs could be explored for use as inhibitors for these cell cycle proteins. Further, we have also highlighted residues which could be important in the designing of pharmacophores against these cell cycle proteins. This is the first report in understanding the mechanism of action of the drugs targeting these cell cycle proteins in leukemia through the visualization of drug-target binding and molecular docking using computational methods.

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Cyclin D1 expression in acute leukemia

Abstract: The biological value of cyclin D1 over expression might be different in AML and ALL.

Cited by 20 publications

References 9 publications

Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

Expression of P-glycoprotein, Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Drug Targets for Cell Cycle Dysregulators in Leukemogenesis: In Silico Docking Studies

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