Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Doxorubicin (Adriamycin, ADR) is an anthracycline antineoplastic with the serious side effect of dose-related cardiomyopathy. A model of ADR cardiotoxicity was created to examine some subcellular toxic effects of ADR with cultured cardiac myocytes (CMCs) exposed to 1 x 10(-7) to 1 x 10(-5) M ADR for 24 to 48 hr. Lactate dehydrogenase (LDH) activity was monitored in the CMC medium to monitor CMC damage as a function of ADR concentration. A four- to eightfold elevation of LDH activity in medium of CMCs exposed to 1 x 10(-6) to 1 x 10(-5) M ADR was found. No change in LDH activity was detected in medium of CMCs exposed to 1 x 10(-7) M ADR or in control CMCs after 24 or 48 h ADR exposure. Data suggest a dose-dependent effect of ADR on LDH activity in CMC medium. Serial monitoring of LDH in media of ADR-exposed CMCs may correlate with other evidence of ADR cardiotoxicity in vitro.
Exp Mol Pathol 1988 Jun
PMID:Lactate dehydrogenase activity in cultured neonatal rat heart cells exposed to doxorubicin. 337 55

A radioactive, photoactive anthracycline analogue, N-(p-azido-[3,5-3H]benzoyl)-daunorubicin (3H-NAB-daunorubicin), was synthesized and characterized by UV-visible absorption and infrared analyses. 3H-NAB-daunorubicin photoaffinity labeling of rat heart homogenates resulted in the identification of two prominently radiolabeled anthracycline-binding polypeptides of 18.3 and 31.2 kDa. Photoaffinity labeling with photoactive doxorubicin (Adriamycin), carminomycin, and nonanthracycline model compounds resulted in a clear structural dependence for binding to the 18.3-and 31.2-kDa species. In the presence of daunorubicin or N-substituted daunorubicin analogues, 3H-NAB-daunorubicin photolabeling of the 18.3-kDa polypeptide was inhibited. Photolabeling was dependent on time of UV light exposure and protein concentration and was unaffected by the presence of nitrene scavengers. The 18.3-kDa polypeptide photolabeling was saturable and reversed by greater than 90% in the presence of a 16-fold molar excess of nonradioactive analogue. Photolabeling of heart subcellular fractions demonstrates that both the 18.3- and 31.2-kDa polypeptides were localized to the inner mitochondrial membrane. Since the anthracyclines are known to have several effects on heart mitochondrial function, the identification of specific polypeptide acceptors using photoactive anthracycline analogues may elucidate biochemical mechanisms of anthracycline cellular activity.
Mol Pharmacol 1986 Oct
PMID:Rat heart anthracycline-binding polypeptides identified by photoaffinity labeling. 346 45

Using a number of derivatives of doxorubicin (Adriamycin) and daunomycin, we have examined how substitution of the anthracycline amine affected net cellular accumulation and cytotoxic potency in HL-60 leukemia cells. Octanol/buffer partitioning demonstrated that each of the derivatives had an amino group titratable between pH 5 and 8, with the exception of derivatives containing a cyanomorpholino-substituted amine, which had a significantly lower pKa value. The steady state cellular drug levels for the Adriamycin and daunomycin series decreased in the following order: N,N-dimethyl-greater than morpholino-greater than parent greater than cyanomorpholino-. Thus, the net cellular accumulation of an anthracycline was found to be influenced by the basicity of the amino group; drugs with a non-basic amino group exhibited reduced uptake. Soft agar clonogenic assays showed the following order of cytotoxicity for both series: cyanomorpholino-much greater than parent greater than morpholino-approximately equal to N,N-dimethyl-. The data demonstrate an inverse correlation between uptake and potency; thus, differences in net cellular accumulation do not account for the order of anthracycline potency.
Mol Pharmacol 1987 May
PMID:Function of the anthracycline amino group in cellular transport and cytotoxicity. 347 65

Mouse NIH 3T3 cells were transformed to multidrug resistance with high-molecular-weight DNA from multidrug-resistant human KB carcinoma cells. The patterns of cross resistance to colchicine, vinblastine, and doxorubicin hydrochloride (Adriamycin; Adria Laboratories Inc.) of the human donor cell line and mouse recipients were similar. The multidrug-resistant human donor cell line contains amplified sequences of the mdr1 gene which are expressed at high levels. Both primary and secondary NIH 3T3 transformants contained and expressed these amplified human mdr1 sequences. Amplification and expression of the human mdr1 sequences and amplification of cotransferred human Alu sequences in the mouse cells correlated with the degree of multidrug resistance. These data suggest that the mdr1 gene is likely to be responsible for multidrug resistance in cultured cells.
Mol Cell Biol 1986 Nov
PMID:Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene. 379 99

Purified bovine cardiac G-actin was interacted with doxorubicin (Adriamycin, ADR), in absence of potassium or magnesium to study ADR's effects on actin polymerization. Actin with ADR (10(-6) M) was incubated with polylysine-coated polystyrene beads and filaments formed were visualized by negative staining electron microscopy (NSEM). ADR-induced actin polymerization was assessed biochemically by ultracentrifugation and analysis of protein content of the supernatant solution. Kinetic assays of turbidity of actin were performed which showed that ADR induced formation of stubby actin polymers which bound to the beads and differed ultrastructurally from the longer actin filaments induced by KCl + MgCl2. Actin content in the supernatant solution decreased after centrifugation (0.8 mg/ml in G-actin to 0.45 mg/ml in actin incubated with 10(-4) M ADR). ADR (10(-4) M) caused increased turbidity of actin of similar magnitude to that induced by actin + KCl + MgCl2. Data support the hypothesis that ADR induces polymerization of cardiac actin in vitro but this polymerization has characteristics which are different from actin polymerization induced by salts.
Exp Mol Pathol 1986 Feb
PMID:Cardiac actin interactions with doxorubicin in vitro. 394 80

The mitochondrial mutation petite was induced in yeast cells by ethidium bromide (EB), Adriamycin (ADR) and 4-nitroquinoline-N-oxide (NQO). In the presence of aspirin in concentrations ranging from 0.1 to 1.0 mg/ml, the mutagenicity of EB and ADR was reversed but petite induction by NQO was unaffected. At these concentrations, aspirin also reversed mitochondrial inhibition by oligomycin, a non-mutagenic inhibitor of the organellar ATPase complex. Cells grown in the presence of aspirin alone showed a significantly higher rate of oxygen uptake than untreated control cultures when the drug concentration ranged from 0.05 to 1.0 mg/ml. At concentrations of 2 mg/ml and above, aspirin inhibited mitochondrial respiration.
Mol Gen Genet 1984
PMID:Effect of aspirin on mitochondrial mutagens in Saccharomyces cerevisiae. 637 78

Adriamycin (doxorubicin) is a broad spectrum anti-tumor antibiotic used to treat cancer patients. However, the potential usefulness of this drug is currently limited by the development of a dose-dependent cardiomyopathic process terminating in severe heart failure. Although several mechanisms have been suggested to explain the pathogenesis of adriamycin-induced cardiomyopathy, free-radical induced oxidative stress appears to play an important role. A concise description of adriamycin-induced cardiomyopathy is provided. Various combination therapies which have been attempted in the past to modulate the adriamycin-induced cardiomyopathy are also discussed. Recently, it has been discovered that probucol, a lipid lowering agent and potent antioxidant, provides complete protection against adriamycin-induced cardiomyopathy in rats without interfering with the anti-tumor properties of this antibiotic. Clinical trials employing adriamycin therapy in combination with probucol are needed to determine the applied value of these laboratory findings.
J Mol Cell Cardiol 1995 Apr
PMID:Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. 756 2

Adriamycin (AD)-Fe3+ caused the inactivation of Na(+)-, K(+)-ATPase and Ca(2+)-ATPase of erythrocyte membranes during lipid peroxidation. AD-Fe3+ also induced the formation of fluorescent substances from the membranes with lipid peroxidation. The fluorescent substances were little extracted by chloroform-methanol, indicating that they were retained in the membranes. Butylated hydroxytoluene and trolox strongly inhibited both the inactivation of these ATPases and the formation of fluorescent substances with lipid peroxidation. Another antioxidant, vitamin E, slightly prevented the damage of the membranes. However, p-nitrophenyl phosphatase activity and acetylcholine esterase have lower or no susceptibility to the membrane lipid peroxidation. These results indicated that the ATPases were very sensitive to lipid peroxidation and that the membranes were modified during the peroxidation reaction.
Res Commun Mol Pathol Pharmacol 1995 Feb
PMID:Adriamycin-Fe(3+)-induced inactivation of enzymes in erythrocyte membranes during lipid peroxidation. 774 51

We have investigated the effect of doxorubicin (Adriamycin) on the yeast Saccharomyces cerevisiae. Drug treatment was found to be cytotoxic to wild-type strains, in a concentration-dependent manner, whereas a petite mutant lacking the cytochrome oxidase (EC 1.9.3.1) subunit IV gene was resistant to doxorubicin. Transformation of the doxorubicin-resistant mutant with a yeast in vivo expression vector harboring the cytochrome oxidase subunit IV gene restored both respiration and sensitivity to doxorubicin. Another petite strain, with a mutation in the mitochondrial adenine nucleotide translocator (pet9), did not display doxorubicin resistance. However, in contrast to the subunit IV mutant, it possesses a functional respiratory chain. We also compared the cytotoxic effect of doxorubicin with those of daunorubicin and mitoxantrone in yeast. We found comparable levels of cytotoxicity for doxorubicin and daunorubicin, which were significantly greater than that for mitoxantrone. Finally, we constructed a yeast strain that overexpresses manganese superoxide dismutase (EC 1.15.1.1), an antioxidant enzyme present in mitochondria. Overexpression of manganese superoxide dismutase protected significantly against doxorubicin and daunorubicin cytotoxicity but only slightly against mitoxantrone cytotoxicity. Collectively, our results provide direct in vivo evidence that superoxide radicals participate in doxorubicin- and daunorubicin-induced cytotoxicity in yeast. Furthermore, these results indicate that mitochondrial respiration is a crucial factor in anthracycline, and perhaps mitoxantrone, cytotoxicity in yeast.
Mol Pharmacol 1994 Dec
PMID:Doxorubicin, daunorubicin, and mitoxantrone cytotoxicity in yeast. 780 47

The genotoxic and cytotoxic effects of etoposide (VP-16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids after different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene-diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S-phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test. DNA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating spermatogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage.
Environ Mol Mutagen 1994
PMID:Etoposide (VP-16) is a potent inducer of micronuclei in male rat meiosis: spermatid micronucleus test and DNA flow cytometry after etoposide treatment. 795 23


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