Gene/Protein Disease Symptom Drug Enzyme Compound
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Doxorubicin (Dx) is used to treat a number of types of cancer. The drug produces many toxic reactions and cardiomyopathy. Many drugs have been used to prevent this myocardial damage caused by peroxidative alterations. EGb 761 is being used to prevent arrhythmias in ischemic myocardium. We decided to establish the tissue protective effect of EGb 761 against myocardial toxic effects of Dx in three groups of rats. Cardiotoxicity signs of Dx were found to be dose-related, beginning at 30 mg/kg dose and being apparent at 45 mg/kg dose. 48 hr after a single i.v. injection, myocardial tissues showed a marked edema, vacuolization and fragmentation. We compared the changes in heart tissue biochemically and histopathologically among the control, Dx treated and EGb 761 (100 mg/kg/d.x 4, i.p.) + Dx treated groups. Biochemical results of CK-MB and MDA values showed a significant decrease in Dx + EGb 761 group when compared with Dx treated group. Histopathologically, myocardial tissues of Dx + EGb 761 treated group were found to have diminished vacuolization and fragmentation. These results suggest that EGb 761 might have the same therapeutic potential in Dx related cardiomyopathy.
Res Commun Mol Pathol Pharmacol 1999
PMID:The effect of EGb 761 on the doxorubicin cardiomyopathy. 1148 48

The cardiotoxicity-induced by chronic treatment of doxorubicin have recently be attributed to free radical formation and/or release of nitric oxide. In the present study, an already established rat model of doxorubicin -induced cardiotoxicity was used. Doxorubicin in a total cumulative dose of 15 mgkg(-1) I.P. given in six equal injections over two week period was administered. After three weeks of doxorubicin administration, the blood pressure, serum lactate dehydrogenase, lipid peroxides, asites fluid and mortality rate were significantly increased. Doxorubicin-induced cardiotoxicity was further confirmed by examining the histopathology of heart sections. Myocardial fibres necrosis with prominent acute inflammatory cells were observed in rats hearts treated with doxorubicin. Aminoguanidine, an inhibitor of nitric oxide synthase, 100 mgkg(-1) injected every other day for two week was given concurrently with doxorubicin. Aminoguanidine given concurrently with doxorubicin return blood pressure, lactate dehydrogenase and lipid peroxides to normal control values. Furthermore, aminoguanidine reduces the mortality rate, ascites fluid formation- induced by doxorubicin and improved the histopathology of rats hearts treated with doxorubicin. In conclusion, inhibition of nitric oxide formation may be beneficial in protecting rat hearts against doxorubicin- induced cardiotoxicity.
Res Commun Mol Pathol Pharmacol 1999
PMID:Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats. 1148 49

Actively dividing cells show progressive loss of telomeric DNA during successive rounds of replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity of primary cells before undergoing cellular senescence. In immortal cells including cancer, cellular senescence can be overcome by reactivation of telomerase or by a telomerase-independent mechanism for lengthening telomeres. In this work, we present a novel example of telomere elongation mechanism in a human stomach adenocarcinoma cell line which was selected for resistance to adriamycin. The resistant cell line (MKN/ADR) had long terminal restriction fragments (TRFs) of up to approximately 50 kb, while its parent cell line (MKN-45) had the TRFs, consisting of a smear extending from approximately 4 to approximately 25 kb. The very large TRFs in MKN/ADR cell line were proven to be telomeric by digestion with the exonuclease Bal31. When telomerase activity was examined using the PCR-based telomeric repeat amplification protocol (TRAP) assay, MKN/ADR cell line showed reduced activity to about 10% of that in MKN-45 cell line. The correlation between reduced telomerase activity and mRNA expression of telomerase subunits in MKN/ADR cell line was assessed by the reverse transcriptase-PCR analysis. The level of human telomerase reverse transcriptase (hTERT) mRNA was lower in MKN/ADR cell line than in MKN-45 cell line. This observation correlates with the finding that telomerase activity is reduced about 10-fold in MKN/ADR cell line. Reverse transcriptase-PCR analysis also revealed a close correlation between telomerase-associated protein (TP1) mRNA expression and telomerase activity in MKN/ADR cell line. In contrast, expression levels of human telomerase RNA (hTR) were identical in both MKN/ADR and MKN-45 cell lines. Taken together, these data suggest that telomeres in MKN/ADR cell line may be regulated through a novel mechanism other than telomerase. Although the basis for telomere elongation mechanism in MKN/ADR cell line is not yet understood, the occurrence of alternative mechanism for telomere elongation in drug-resistant cancer cells may have an important implication for use of telomerase inhibitors in human cancer treatment.
Mol Cells 2002 Apr 30
PMID:A novel telomere elongation in an adriamycin-resistant stomach cancer cell line with decreased telomerase activity. 1201 44

Doxorubicin is a chemotherapeutic agent that can induce cardiotoxicity and congestive heart failure (CHF). In this study we tested whether intracoronary Akt1 gene delivery could inhibit doxorubicin-induced CHF. Saline or a replication defective adenoviral vector expressing constitutively-active Akt1 (myrAkt) or beta-galactosidase (betagal) was delivered to the myocardium of 8 week old rats one day prior to initiating doxorubicin administration. In animals receiving saline or betagal, doxorubicin resulted in significant decreases in cardiac function and retarded post-natal heart growth at the 5 weeks time point. In contrast, transduction of myrAkt protected hearts against doxorubicin-induced decreases in fractional shortening and cardiac index, and improved left ventricular function at 5 weeks time point. Delivery of myrAkt also reversed the doxorubicin-induced reduction in post-natal heart growth and diminished lung edema. These data show that myocardial Akt can inhibit doxorubicin-induced reductions in cardiac function and growth, suggesting that manipulation of this signaling pathway may have utility for the treatment of congestive heart failure.
J Mol Cell Cardiol 2002 Oct
PMID:Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth. 1239 81

The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment, p53 protein levels increase in the nucleus, leading to the induction of its transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53 (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis. Cytochrome c and caspase-9 function downstream of p53 in mediating the drug-triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome c release and caspase-9 activation. Furthermore, drug-induced cell death can be prevented by expression of a dominant-negative mutant of caspase-9. These findings define a molecular pathway for mediating DNA damaging drug-induced apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells.
Mol Cancer Ther 2002 Jul
PMID:p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells. 1247 64

Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.
Mol Endocrinol 2003 May
PMID:Estradiol rapidly activates Akt via the ErbB2 signaling pathway. 1527 3

As telomeres play a role in protecting DNA, there is the possibility that telomerase activity is involved with cellular response to DNA-damaging agents. This study was designed to investigate the association between telomerase and the doxorubicin altered cell cycle in drug resistant gastric carcinoma cell lines. Three doxorubicin resistant gastric carcinoma cell lines and their parent cell lines (SNU-1, SNU-16 and SNU-620) were incubated with doxorubicin at the final concentration induced resistance and ten times final concentration for 24 h. Telomerase activity and hTERT mRNA expression were lowered by doxorubicin treatment in parent cell lines, but in drug resistant cell lines, telomerase activity and hTERT mRNA expression were not repressed by doxorubicin treatment. Bcl-2 protein expression, which is known to regulate telomerase activity, did not change in doxorubicin resistant cell lines but decreased in parent cell lines by doxorubicin treatment. Cell cycle analysis revealed that the parent cell lines had an increased fraction of cells in G2/M phase after doxorubicin treatment and doxorubicin resistant cell lines had maintained fractions in G0/G1 phase. Doxorubicin treatment did not alter cyclin B or cdc2 protein level, which is known as the essential component of G2/M transition. G2/M arrest in the parent cell lines was associated with an increase in inhibitory phosphorylation of Tyr15 on cdc2. In summary, the parent cell lines showed G2/M arrest and a reduction of telomerase activity after doxorubicin treatment. In contrast, reduced telomerase activity, Bcl-2 expression and G2/M arrest after doxorubicin treatment did not appear in resistant cell lines. Therefore, relative resistance to doxorubicin may be related to high levels of bcl-2 or intact cell cycle and consequently high telomerase activity.
Int J Mol Med 2003 Mar
PMID:Telomerase activity, expression of Bcl-2 and cell cycle regulation in doxorubicin resistant gastric carcinoma cell lines. 1257 37

Doxorubicin is co-transported with glutathione by several multidrug resistance proteins (MRPs). In order to check whether weak non-covalent aggregates between doxorubicin and glutathione can be formed, which might be substrates for the transporter, the effect of glutathione on the partition coefficient of doxorubicin was studied. No evidence of an effect of glutathione (at levels up to 20 microM) on the partition coefficient of doxorubicin was found in the pH range of 4.0-7.4. These results indicate that non-covalent doxorubicin-glutathione complexes do not form.
Cell Mol Biol Lett 2003
PMID:There is no evidence for the existence of complex formation between doxorubicin and glutathione. 1281 65

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in several organs. Adriamycin nephrotoxicity has been recently documented in a variety of animal species. The present study was designed to investigate the effect of lipoic acid on the nephrotoxic potential of adriamycin. The study was carried out with adult male albino rats of Wistar strain. Test animals were divided into four groups of six rats each as follows: Group I (control) received only normal saline throughout the course of the experiment. Group II (ADR) received intravenous injections of adriamycin through the tail vein (1 mg kg(-1) body wt day(-1)) once a week for a period of 12 weeks. Group III (LA) received lipoic acid (35 mg kg(-1) body wt day(-1)) intraperitoneally once a week for a period of 12 weeks. Group IV (ADR + LA) received a single injection of lipoic acid intraperitoneally 24 h prior to the administration of adriamycin through the tail vein once a week for a period of 12 weeks. Intravenous injections of adriamycin resulted in decreased activities of the glycolytic enzymes; hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase in the rat renal tissue. The gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, showed a decline in their activities on adriamycin administration. The transmembrane enzymes namely the Na+,K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and the brush-border enzyme alkaline phosphatase also showed a decrease in their activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush-border membrane damage. Decreased activities of the TCA cycle enzymes isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, suggest a loss in mitochondrial function and integrity. Nephrotoxicity was evident from the increased excretions of N-acetyl-beta-D-glucosaminidase and gamma-glutamyl transferase in the urine of adriamycin administered rats. These biochemical disturbances were effectively counteracted on pre-treatment with lipoic acid, which brought about an increase in the activities of glycolytic enzymes, ATPases and the TCA cycle enzymes. On the other hand, the gluconeogenic enzymes showed a further decrease in their activities on lipoic acid pretreatment. LA pretreatment also restored the activities of the urinary enzymes to normal. These observations shed light on the nephroprotective action of lipoic acid rendered against experimental aminoglycoside toxicity.
Mol Cell Biochem 2003 May
PMID:The influence of lipoic acid on adriamycin induced nephrotoxicity in rats. 1284 26

Insulin-like growth factor-1 (IGF 1) suppresses myocardial apoptosis and improves myocardial function in experimental models of cardiomyopathy. Apoptosis is triggered by mitochondria dysfunction and subsequent activation of caspases. We had previously shown that IGF 1 inhibited cardiomyocyte apoptosis via suppression of caspase, however, how IGF 1 and its signaling pathway modulates mitochondria function in cardiac muscle is not yet known. In this study we investigated how IGF 1 signaling modulates mitochondria membrane depolarization in the cardiomyocytes treated with doxorubicin. Doxorubicin rapidly induced loss of mitochondria electrochemical gradient and triggered mitochondria depolarization in primary cardiomyocytes, whereas addition of IGF 1 restored mitochondria electrochemical gradient. The effects of IGF 1 was blocked by a chemical inhibitor of PI 3 kinase and a dominant negative Akt, suggesting that IGF 1 signaling to mitochondria involves the PI 3 kinase-Akt pathway. Transducing cardiomyocytes with constitutive active PI 3 kinase partially restored the mitochondria electrochemical gradient in doxorubicin-treated cells. These findings provide direct evidence that IGF 1 modulation of mitochondria function is mediated through activation of PI 3 kinase and Akt. Additional experiments using agonist and antagonist of mitochondria K(ATP) channel suggest that IGF 1 signaling to mitochondria membrane does not directly involve K(ATP) channel. These findings suggest that cytosolic signaling to mitochondria may play a fundamental role in the cardiotoxic actions of doxorubicin and cardioprotective actions of IGF 1.
Mol Cell Endocrinol 2003 Jul 31
PMID:Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway. 1289 May 71


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