Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) enhances high-dose Ara-C-induced programmed cell death or apoptosis in human myeloid leukemia cells

Bhalla, Kapil N.; Tang, Caroline; Ibrado, Ana Maria; Grant, Steven; Tourkina, Elena; Holladay, Charles; Hughes, Monty; Mahoney, Mary Ella; Huang, Yue

doi:10.1182/blood.v80.11.2883.bloodjournal80112883

Cited by 21 publications

(8 citation statements)

References 26 publications

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“…Thus, we generated adenoviral vectors expressing two additional hypothetical IL‐12 family heterodimers not yet found naturally, termed IL‐Y (p40 and p28) and IL‐X (Ebi3 and p19), as single chain molecules. Other studies have shown that single chain fusions of G‐CSF and GM‐CSF and G‐CSF and IL‐3 are biologically active and that single chain IL‐12 and Il‐23 are as or more active than the normal dimeric cytokine . Our analysis suggests that IL‐Y in particular is able to stimulate a specific subset of cytokines/chemokines, distinct from the IL‐12 family members.…”

Section: Discussionmentioning

confidence: 49%

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IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

et al. 2015

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The IL-12 family of heterodimeric cytokines, consisting of IL-12, IL-23, IL-27, and IL-35, has important roles in regulating the immune response. IL-12 family members are comprised of a heterodimer consisting of α and β chains: IL-12 (p40 and p35), IL-23 (p40 and p19), IL-27 (Ebi3 and p28), and IL-35 (Ebi3 and p35). Given the combinatorial nature of the IL-12 family, we generated adenoviral vectors expressing two putative IL-12 family members not yet found naturally, termed IL-X (Ebi3 and p19) and IL-Y (p40 and p28), as single-chain molecules. scIL-Y, but not scIL-X, was able to stimulate significantly a unique cytokine/chemokine expression profile as well as activate STAT3 in mice, in part, through a pathway involving IL-27Rα in splenocytes. Adenoviral-mediated, intra-tumoral delivery of scIL-Y increased tumor growth in contrast to the anti-tumor effects of scIL-12 and scIL-23. Similarly, treatment of pre-diabetic non-obese diabetic (NOD) mice by intravenous injection of Ad.scIL-Y prevented the onset of hyperglycemia. Analysis of cells from Ad.scIL-Y-treated NOD mice demonstrated that scIL-Y reduced expression of inflammatory mediators such as IFN-γ. Our data demonstrates that a novel, synthetic member of the IL-12 family, termed IL-Y, confers unique immunosuppressive effects in two different disease models and thus could have therapeutic applications.

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Section: Discussionmentioning

confidence: 49%

“…The anti‐tumor activities of IL‐12 and IL‐23 also were significantly enhanced when their two subunits were expressed as a single chain using a 15 amino acid linker . The enhanced function of the linked cytokines is reminiscent of previous studies with IL‐12 (p35 and p40), G‐CSF (GM‐CSF fusion), and GM‐CSF (IL‐3 fusion) .…”

Section: Introductionmentioning

confidence: 59%

IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

et al. 2015

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“…It has been demonstrated that expression of Bcl‐2, an antiapoptotic protein, is increased following short‐term phorbol ester treatment in the immature Ramos B‐cell line, and up‐regulation of expression of Bcl‐2 increases cell resistance to apoptosis [24, 25]. In HL‐60 cells, induction of apoptosis by ara‐C has been shown to be associated with down‐regulation of Bcl‐2 [26]. However, apoptosis induced by photosensitization is a rapid process, which does not require new protein synthesis [4].…”

Section: Discussionmentioning

confidence: 99%

Activation of protein kinase C is required for protection of cells against apoptosis induced by singlet oxygen

1998

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We evaluated the role of protein kinase C (PKC) in the regulation of apoptosis triggered by singlet oxygen. Activation of PKC by short-term 12-O-tetradecanoyl phorbol 13-acetate (TPA) treatment inhibited apoptosis, whereas inhibition of PKC with several inhibitors potentiated this process. The antiapoptotic effect of TPA was accompanied by phosphorylation of extracelluar signal-regulated kinase 1/2 (ERK1/2). Pretreatment of cells with MEK inhibitor, PD98059, inhibited TPA-induced phosphorylation of ERK1/2 and the cytoprotective ability of TPA. These results suggest that activation of PKC in HL-60 cells confers protection against apoptosis induced by singlet oxygen and that ERK1/2 mediates antiapoptotic signaling of PKC.z 1998 Federation of European Biochemical Societies.

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“…DNA from both supernatant and pellet was precipitated by addition of 1 N perchloric acid. The DPA method (Bhalla et al, 1992) was used for measurement of DNA content. The percent change of DNA fragments was calculated with the following equation:…”

Section: Quantitative Analysis Of Fragmented Dnamentioning

confidence: 99%

Intracellular Ca2 release mediates ursolic acid–induced apoptosis in human leukemic HL‐60 cells

Baek¹,

Lee²,

Kang³

et al. 1997

Int. J. Cancer

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The effect of ursolic acid (UA) on tumor cell apoptosis was investigated using HL-60 human promyelocytic leukemia cells as a model cellular system. Treatment with UA resulted in a concentration-dependent decreased cell viability assessed by MTT assay. UA also induced genomic DNA fragmentation, a hallmark of apoptosis, indicating that the mechanism by which UA induced cell death was through apoptosis. Ursolic acid (UA), a pentacyclic triterpene acid, has been isolated from many kinds of medicinal plant, such as Eriobotrya japonica, Rosmarinus offıcinalis and Glechoma hederaceae. UA has been reported to produce anti-tumor activities, including inhibition of skin tumorigenesis (Huang et al., 1994) and inhibition of tumor promotion (Tokuda et al., 1986). It also induced tumor cell differentiation by regulation of the expression of differentiationspecific genes in mouse F9 teratocarcinoma cells (Lee et al., 1994). In addition, UA was shown to possess an anti-angiogenic effect in chick chorioallantoic membrane (Sohn et al., 1993) and an anti-invasive activity in HT1080 human fibrosarcoma cells (Cha et al., 1996).Apoptosis has been reported to be involved in the carcinogenic process (Thompson, 1995;Isaacs, 1993) and in tumor therapy and prevention (Bursch et al., 1992). Many of the presently used chemotherapeutic agents of cancer induce apoptosis (Miyashita and Reed, 1993). Increased intracellular Ca 2ϩ concentration has been demonstrated to act as an important mediator of apoptosis in a variety of cells (Dow, 1995).Retinoic acid, a differentiation-inducing agent, has been shown to induce tumor cell apoptosis in mouse F9 teratocarcinoma cells (Atencia et al., 1994). Since UA was reported to have an activity of tumor cell differentiation (Lee et al., 1994), in this study, we investigated the possibility that UA can induce tumor cell apoptosis using HL-60 cells as a model cellular system. We also examined the role of intracellular Ca 2ϩ signals in the apoptosis induced by UA. MATERIAL AND METHODS MaterialThe HL-60 human promyelocytic leukemia cell line was purchased from the ATCC (Rockville, MD). The powder for RPMI 1640 medium, FBS and antibiotics (penicillin and streptomycin mixture) were purchased from GIBCO (Grand Island, NY). UA, dantrolene (Dant), 3,4,5-trimethoxybenzoic acid-8-(diethylamino)-octyl ester (TMB-8), ruthenium red (RR), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and diphenylamine (DPA) were obtained from Sigma (St. Louis, MO). Bis-(o-aminophenoxy)-ethane-N,N,NЈ,NЈ-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) and 1-(2,5-carboxyoxazol-2-yl-6-aminobenzfuran-5-oxyl)-2-(2Ј-amino-5Ј-methylphenoxy)-ethane-N,N,NЈ,NЈ-tetraacetoxymethyl ester (Fura-2/AM) were from Molecular Probes (Eugene, OR). Unless otherwise indicated, propidium iodide (PI) and all other chemicals were the purest grade available and were obtained from Sigma. UA and TMB-8 were dissolved in ethanol. Dant and BAPTA/AM were dissolved in DMSO, and other drugs were dissolved in distilled water. These stock solutions were...

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Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) enhances high-dose Ara-C-induced programmed cell death or apoptosis in human myeloid leukemia cells

Cited by 21 publications

References 26 publications

IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

IL‐Y, a synthetic member of the IL‐12 cytokine family, suppresses the development of type 1 diabetes in NOD mice

Activation of protein kinase C is required for protection of cells against apoptosis induced by singlet oxygen

Intracellular Ca2 release mediates ursolic acid–induced apoptosis in human leukemic HL‐60 cells

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