Cellular responses to external ATP which precede an increase in nucleotide permeability in transformed cells

Weisman, Gary A.; De, Barun K.; Friedberg, Ilan; Pritchard, Robert S.; Heppel, Leon A.

doi:10.1002/jcp.1041190211

Cited by 57 publications

(47 citation statements)

References 35 publications

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“…Several other reports suggest that expression is not exclusive to this lineage as there is evidence of P2X 7 R expression on sperm (52) and some cancer cells of non-hematopoietic lineage (53). Despite extensive studies, the physiological function of this receptor remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Altered Cytokine Production in Mice Lacking P2X7Receptors

Solle¹,

Labasi²,

Perregaux³

et al. 2001

Journal of Biological Chemistry

838

742

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The P2X 7 receptor (P2X 7 R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1␤ post-translational processing, we have generated a P2X 7 R-deficient mouse line. P2X 7 R ؊/؊ macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1␤ comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1␤ produced by the P2X 7 R ؊/؊ cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1␤ from P2X 7 R ؊/؊ macrophages. In response to in vivo lipopolysaccharide injection, both wild-type and P2X 7 R ؊/؊ animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATPtreated, LPS-primed P2X 7 R ؊/؊ animals. Absence of the P2X 7 R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency, in vivo cytokine signaling cascades are impaired in P2X 7 R-deficient animals. Together these results demonstrate that P2X 7 R activation can provide a signal that leads to maturation and release of IL-1␤ and initiation of a cytokine cascade.

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Section: Discussionmentioning

confidence: 99%

Altered Cytokine Production in Mice Lacking P2X7Receptors

Solle¹,

Labasi²,

Perregaux³

et al. 2001

Journal of Biological Chemistry

838

742

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“…0.05 mM). Our previous studies have shown that the increase in the membrane permeability is preceded by ion fluxes across the cell membrane and a reduction of the membrane potential [16,18,19]. The membrane potential was measured by the accumulation of the hydrophobic cation TPP + in the cells.…”

Section: Figurementioning

confidence: 99%

Combined effects of ATP and its analogs on the membrane permeability in transformed mouse fibroblasts

Arav

Friedberg

1996

FEBS Letters

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Extracellular ATP (0.6 mM) induces a marked decrease in the membrane potential, followed by an increase in cell membrane permeability in transformed mouse fibroblasts. The effects of the ATP analogs, pICHaIppA and p[NH]ppA (0.6 m VI), on the membrane potential and permeability are much less pronounced. ATP at 0.05 mM has no effect by itself, but markedly increases the analog-induced membrane potential di~ipation and permeability. The data suggest that ATP-induced membrane permeation is composed of two processes: One is common to ATP and its analogs and appears to be a receptormediated process. The second is unique for ATP, effective even at low concentration (0.05 mM), and might be mediated by cell surface enzymes, for which ATP, but not its analogs, serves as a substrate.

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“…The expanded erythrocyte ATP pools are stable over a period of hours, while slowly releasing micromolar amounts of ATP into the blood plasma compartment, leading to severalfold increases in plasma (extraceilular) ATP levels. Based on previous studies in which [1][2][3][4][5] ,uM extracellular ATP effectively inhibited the growth of a variety oftumor cells in several in vitro systems, it is suggested that similar levels of ATP in blood plasma account for the anticancer activities observed in a murine host.…”

mentioning

confidence: 99%

“…Extensive in vitro studies by Heppel and his colleagues (1,2) and our group (3,4) have shown the cytostatic and cytotoxic properties of extracellular ATP against a wide variety of animal and human tumor cells under several culture conditions. Both the selectivity of the tumor growth-inhibitory properties of exogenous ATP against transformed but not normal cells (1)(2)(3) and the ability of low (1-5 ,uM) concen-trations of ATP to effectively inhibit the growth of human tumor cells in soft agar cultures (4) suggested the possible therapeutic efficacy of ATP against experimental tumors grown in a host.…”

mentioning

confidence: 99%

“…Both the selectivity of the tumor growth-inhibitory properties of exogenous ATP against transformed but not normal cells (1)(2)(3) and the ability of low (1-5 ,uM) concen-trations of ATP to effectively inhibit the growth of human tumor cells in soft agar cultures (4) suggested the possible therapeutic efficacy of ATP against experimental tumors grown in a host. One of us has shown (5) that daily i.p.…”

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confidence: 99%

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Anticancer activities of adenine nucleotides in mice are mediated through expansion of erythrocyte ATP pools.

Rapaport

Fontaine

1989

Proc. Natl. Acad. Sci. U.S.A.

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x C57BL/6 6) F1 (CB6F1) mice and human pancreatic adenocarcinoma, CAPAN-1, xenografts in athymic nude mice. Administration (i.p.) of AMP or ATP in large volumes of saline resulted in increases in levels of ATP in whole blood (cellular) and the plasma compartment (extracellular). Treatment of mice with AMP or ATP yielded increases in plasma levels of ATP from a basal level of about 0.8 1LM to 2-5 ktM.These expanded ATP pools were achieved for several hours after a single i.p. injection of AMP or ATP and were obtained without long-lasting toxicity toward the host (5). We suggested that the extracellular ATP generated in the blood plasma of tumor-bearing hosts affects the growth of tumor cells by mechanisms that were identified by the in vitro studies (1-4), although host-mediated mechanisms cannot be ruled out, since ATP is known to influence several physiological systems that may affect tumor growth (6).We now have identified a biological mechanism that accounts for the generation of increased blood plasma ATP concentrations after i.p. administration of AMP or ATP (but not adenosine) into mice. The potential clinical utility ofAMP or ATP treatments is demonstrated by the significant inhibition of CT26 colon adenocarcinoma growth in CB6F1 mice when the treatment is initiated after the tumors became palpable. In addition, an unexpected effect of adenine nucleotides is their ability to slow the rate of weight loss in mice bearing relatively large CT26 tumors. This phenomenon is not related to the tumor growth-inhibitory effects of these compounds and may be related to an effective introduction of purines into the host and their effective distribution into host tissues, thus slowing down the nutritional depletion of host compartments by the fast-growing tumor (7). MATERIALS AND METHODSSolutions of nucleotides in saline were prepared as described (5). Culture conditions of CT26 cells and tumor inoculations in CB6F1 mice (The Jackson Laboratory) followed published procedures (5).Experimental Protocol. Tumors were inoculated by injections of 2.5 x 105 CT26 cells (>90% viability) in 50 /.l of phosphate-buffered saline into the right hind footpad of CB6F1 mice. Treatments were initiated at a variety of times after inoculation of the tumors. The injection schedules started either 1 or 5 days after tumor inoculation (when none of the tumors were palpable) or when the tumors were clearly palpable (average calculated weight of 100 mg), which occurred in 100% of the inoculated mice after 8-11 days. Mice were randomized, divided into groups, and injected daily with 2.2 ml of saline, adenosine, AMP, or ATP (compounds were in sterile saline solutions at concentrations of 25 mM, with AMP and ATP solutions adjusted to pH 6.2). Injections were administered i.p. with 30-gauge needles, and mice were lightly anesthetized with ether. Mice were weighed, and tumor sizes were measured before the start of the treatment schedule and every 3 days during and after the treatment schedule. These determinations were performed before injections du...

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Cellular responses to external ATP which precede an increase in nucleotide permeability in transformed cells

Cited by 57 publications

References 35 publications

Altered Cytokine Production in Mice Lacking P2X7Receptors

Altered Cytokine Production in Mice Lacking P2X7Receptors

Combined effects of ATP and its analogs on the membrane permeability in transformed mouse fibroblasts

Anticancer activities of adenine nucleotides in mice are mediated through expansion of erythrocyte ATP pools.

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