Doxorubicin interactions at the membrane: Evidence for a biphasic modulation of inositol lipid metabolism

doi:10.1016/0277-5379(91)90094-T

European Journal of Cancer and Clinical Oncology

Volume 27, Issue 10, October 1991, Pages 1263-1268

European Journal of ...

https://doi.org/10.1016/0277-5379(91)90094-T Get rights and content

Abstract

Doxorubicin, when incubated for 30 minutes with [³²P]-labelled human erythrocyte membrane vesicles, produced an elevation of [³²P]inositol-1,4,5-trisphosphate levels. The maximum rise was obtained with 10⁻⁸ mol/l doxorubicin [132 (S.E. 13%) of control, n = 6, P = 0.001]. However, when the inositol lipids were examined, there was no evidence that doxorubicin stimulated the breakdown of [³²P]phosphatidylinositol-4,5-bisphosphate under resting conditions, suggesting that the elevated levels of [³²P]inositol 1,4,5-trisphosphate were not the result of the stimulation of phospholipase C. Instead, it was found that the dephosphorylation of inositol 1,4,5-trisphosphate by a 5′-phosphomonoesterase was partially inhibited by 10⁻⁸ mol/l doxorubicin so that the rise in [³²P]inositol 1,4,5-trisphosphate resulted from the inhibition of the breakdown of constitutively released [³²P] inositol 1,4,5-trisphosphate. Similar data was also obtained with another aminoglycoside antibiotic, neomycin. The release of [³²P] inositol 1,4,-bisphosphate and [³²P] inositol 1,4,5-trisphosphate and the breakdown of the inositol lipids in response to calcium (2.5 × 10⁻⁴ and 10⁻³ mol/l) stimulation was enhanced by doxorubicin (10⁻⁶ to 10⁻¹² mol/l). These effects on resting and stimulated inositol lipid metabolism are discussed with reference to the paradoxical effects of doxorubicin to both stimulate and inhibit proliferation, according to concentration.

References (48)

W.E Ross
DNA topoisomerases as targets for cancer chemotherapy
Biochem Pharmacol
(1985)
S.A Murphree et al.
Adriamycin induces changes in the surface membrane on Sarcoma 180 ascites cells
Biochim Biophys Acta
(1981)
J.M Siegfried et al.
The role of membranes in the mechanism of action of the antineoplastic agent adriamycin
J Biol Chem
(1983)
D.E Ingber et al.
Tension and compression as basic determinants of cell form and function
E Goormaghtigh et al.
Anthracycline glycoside-membrane interactions
Biochim Biophys Acta
(1984)
C.E Bazenet et al.
Erythroid membrane-bound protein kinase binds to a membrane component and is regulated by phosphoinositol 4,5-bisphosphate
J Biol Chem
(1990)
N Yonezawa et al.
Inhibition of the interactions of cofilin, destrin, and deoxyribonuclease I with actin phosphoinositides
J Biol Chem
(1990)
T.A Rooney et al.
Short chain alcohols activate guanine nucleotide dependent phosphoinositidase C in turkey erythrocyte membranes
J Biol Chem
(1989)
T.K Harden et al.
Turkey erythrocyte membranes as a model for regulation of phospholipase C by guanine nucleotides
J Biol Chem
(1987)
C.-H Heldin et al.
Subversion of growth regulatory pathways in malignant transformation
Biochim Biophys Acta
(1987)

A Schibeci et al.

The action of neomycin on the metabolism of polyphosphoinositides in the guinea pig kidney

Biochem Pharmacol

(1977)

D.H Carney et al.

Phosphoinositides in mitogenesis: neomycin inhibits thrombin-stimulated phosphoinositide turnover and initiation of cell proliferation

Cell

(1985)

M Prentki et al.

Neomycin: a specific drug to study the inositol-phospholipid signalling system?

FEBS Lett

(1986)

S.R Keyes et al.

The effects of adriamycin on intracellular calcium concentrations on L1210 murine leukemia cells

Eur J Cancer Clin Oncol

(1987)

E Herrmann et al.

Stimulation and inhibition of human platelet membrane high-affinity GTPase by neomycin

FEBS Lett

(1988)

N Wang et al.

Tubulin binds specifically to the signal-transducing proteins, G_sx and G_ix 1

J Biol Chem

(1990)

C Na et al.

Chemical study of daunomycin-tubulin interactions

Arch Biochem Biophys

(1977)

F Arcamone

Doxorubicin, Anticancer antibiotics

T.R Tritton et al.

Cell surface membranes as a chemotherapeutic target

T.R Tritton et al.

Adriamycin: a proposal on the specificity of drug action

Biochem Biophys Res Commun

(1975)

J Posada et al.

Protein kinase C in adriamycin action and resistance in mouse sarcoma 180 cells

Cancer Res

(1989)

S.C Barranco et al.

Survival and cell kinetic effects of adriamycin on mammalian cells

Cancer Res

(1973)

B Barlogie et al.

The effect of adriamycin on the cell cycle traverse of a human lymphoid cell line

Cancer Res

(1976)

K.W Lanks et al.

DNA synthesis by L929 cells following doxorubicin exposure

Cancer Res

(1990)

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Specialist interest articleDoxorubicin interactions at the membrane: Evidence for a biphasic modulation of inositol lipid metabolism

Abstract

Biochem Pharmacol

Biochim Biophys Acta

J Biol Chem

Biochim Biophys Acta

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Biochem Pharmacol

Cell

FEBS Lett

Eur J Cancer Clin Oncol

FEBS Lett

J Biol Chem

Arch Biochem Biophys

Doxorubicin, Anticancer antibiotics

Cell surface membranes as a chemotherapeutic target

Adriamycin: a proposal on the specificity of drug action

Biochem Biophys Res Commun

Protein kinase C in adriamycin action and resistance in mouse sarcoma 180 cells

Cancer Res

Survival and cell kinetic effects of adriamycin on mammalian cells

Cancer Res

The effect of adriamycin on the cell cycle traverse of a human lymphoid cell line

Cancer Res

DNA synthesis by L929 cells following doxorubicin exposure

Cancer Res

Specialist interest article
Doxorubicin interactions at the membrane: Evidence for a biphasic modulation of inositol lipid metabolism