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Background: Despite recent progress in molecular-targeted therapies, breast cancer remains the primary leading cause of cancer related death among women worldwide. Breast cancer stem cells (BCSCs) are believed to be responsible for therapy resistance and cancer recurrence. We recently demonstrated that human BCSCs (CD24-/CD44+) could survive better than their counterpart non-BCSCs (CD24-/CD44-) when treated with rotenone, possibly due to lower levels of reactive oxygen species (ROS) production, high expression of antioxidant manganese superoxide dismutase (MnSOD), and anti-apoptotic survivin. The aim of this study was to verify the role of survivin on human BCSCs survival under oxidative stress modulation by suppressing its expression using YM155, a survivin inhibitor., Methods: Human BCSCs (ALDH+ cells) were treated with YM155 for 24 h prior to treatment with rotenone for a further 6 h. We determined intracellular superoxide levels were determined using dihydroethidium assay, survivin and MnSOD expression using qRT-PCR, survivin protein level using ELISA, as well as cell viability using trypan blue exclusion and acridine orange/ethidium bromide apoptosis assay., Results: Suppression of survivin expression using YM155 could reduce the survival of rotenone-treated BCSCs, which may be associated with oxidative stress modulation, as shown by increased ROS levels and decreased MnSOD expression. We confirm that survivin is responsible for maintaining BCSCs survival under oxidative stress modulation. Furthermore, YM155 could modulate oxidative stress in BCSCs by reducing MnSOD expression and increasing ROS levels., Conclusion: YM155 treatment could be used to overcome BCSCs resistance to oxidative stress-based anticancer therapies.

Aim: to analyze the role of allopurinol in reducing the ischemia-reperfusion injury, and to confirm the HIF-1 binding activity changes during the surgical correction of tetralogy of fallot (TF)., Methods: randomized, double-blind experimental study on patients undergoing surgical correction of TF in the Integrated Cardiovascular Services, Cipto Mangunkusumo Hospital from September 2009-May 2010. Patients were randomly divided into two groups. The first group was given 10 mg/kg body weight of allopurinol 3 times before undergoing operation (n=13) and the other group was given placebo (n=13). Tissue specimen from right ventricular muscle were taken for measurement of reactive oxygen species (ROS) expression and blood specimens from intra-coronary sinus for measurement of TNF-, superoxide dismutase (SOD), and malondialdehyde (MDA)., Results: cardiomyocytes expressing ROS in placebo group increased (41.37±29.29%; 42.61±22.82% and 53.81±25.76%), while in allopurinol group decreased (44.68±19.79%, 56.87±15.50%, and 47.98±22.52%). Concentration of TNF- tend to decrease in allopurinol group, while it tended to increase in the placebo goup. Concentration of SOD increased in the allopurinol group, while in the placebo group there were no significant changes. Concentration of MDA was highly increased in the placebo group (1.75 pmol/mg; 2.37 pmol/mg; 2.72 pmol/mg; 4.82 pmol/mg), but statistically it was not significant. On the other hand, there was no significant change of MDA concentration in the allopurinol group. Expression of HIF-1 in TF patients decreased significantly (p=0.026) from pre ischemic phase to ischemic phase, but it increased in the reperfusion phase (0.95 OD/mg protein, 0.52 OD/mg protein, 0.9 OD/mg protein)., Conclusion: pre-surgical oral allopurinol treatment reduced ischemia-reperfusion injury during TF surgical correction, as indicated by the decrease in the number of cardiomyocytes expressing ROS, reducing TNF-, SOD, and MDA concentration in blood. There was a decrease in HIF-1 concentration in cardiomyocytes of the right ventricle during ischemic phase.

Lung cancer is the primary cause of cancer death in the world. Although it is well established that tobacco smoke causes lung cancer, not all smokers develop lung cancer. Manganese superoxide dismutase (MnSOD), a major determinant of antioxidants in matrix mitochondria, plays a pivotal role in eliminating anion superoxide free radical generated from the tobacco smoke. The aim of this study was to analyze the enzyme activity of MnSOD in blood of lung cancer patients with a smoking history in relationship to oxidative stress. Samples were taken from leukocyte cells of 20 lung cancer patients in Persahabatan Hospital Jakarta. Control groups included 50 healthy smokers and 50 non smokers, all aged over 40 years. The MnSOD activity determined biochemically based on the inhibition of xanthin oxidase, of lung cancer patients was lower than the control group's (p<0.001). Plasma MDA levels, determined by reaction with thiobarbituric acid (TBA), were not significantly different (p=0.479), whereas plasma carbonyl levels were elevated (p=0.003). Free radical production in lung cancer patients thus appeared high. Smoker controls also tended to exhibit lower MnSOD and higher carbonyl radicals than their non-smoking counterparts. Continue cigarette smoke exposure may increase production of ROS and bring about a reduction of MnSOD, which could play a role in lung cancer development.

Cyntia Gracesella Patintingan,1 Melva Louisa,2 Vetnizah Juniantito,3 Wawaimuli Arozal,2 Silmi Hanifah,1 Septelia Inawati Wanandi,4 Rajarajan Thandavarayan5 1Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 2Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 3Department of Veterinary Clinic Reproduction and Pathology, Faculty of Veterinary Medicine, Agriculture Institute of Bogor, Bogor, Indonesia; 4Department of Biochemistry and Molecular Biology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 5Department of Cardiovascular Sciences Houston Methodist Research Institute, Houston, TX, USACorrespondence: Melva Louisa, Department of Pharmacology and Therapeutics Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia, Tel +62-21-31930481, Email melva.louisa@gmail.comBackground: Doxorubicin, an anthracycline class of anticancer, is an effective chemotherapeutic agent with serious adverse effects, mainly cardiotoxicity. Several possible causes of doxorubicin cardiotoxicity are increased oxidative stress, nucleic acid and protein synthesis inhibition, cardiomyocyte apoptosis, and mitochondrial biogenesis disruptions. Moringa oleifera (MO), a naturally derived medicine, is known for its antioxidative properties and activity in alleviating mitochondrial dysfunction. To determine the potency and possible cardioprotective mechanism of MO leaves aqueous extract via the mitochondrial biogenesis pathway in doxorubicin-induced rats.Methods: Twenty-four Sprague-Dawley rats were divided into four groups of six. The first group was normal rats; the second group was treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly for four weeks; the third and fourth groups were treated with doxorubicin 4 mg/kg BW intraperitoneally once weekly, and MO leaves extract at 200 mg/kg BW or 400 mg/kg BW orally daily, for four weeks. At the end of the fourth week, blood and cardiac tissues were obtained and analyzed for cardiac biomarkers, mitochondrial DNA copy number, mRNA expressions of peroxisome-activated receptor-gamma coactivator-1 alpha (PGC-1α), the nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), caspase 3, the activity of glutathione peroxidase (GPx), levels of 8-hydroxy-2-deoxyguanosine (8-OH-dG), and malondialdehyde.Results: MO leaves extract was shown to decrease biomarkers of cardiac damage (LDH and CK-MB), malondialdehyde levels, and GPx activity. These changes align with the reduction of mRNA expressions of caspase-3, the increase of mRNA expressions of PGC-1α and Nrf2, and the elevation of mitochondrial DNA copy number. MO leaves extracts did not influence the mRNA expressions of superoxide dismutase 2 (SOD2) or the levels of 8-OH-dG.Conclusion: Moringa oleifera leaves extract ameliorates doxorubicin-induced cardiotoxicity by reducing apoptosis and restoring gene expression of PGC-1α and Nrf2, a key regulator in mitochondrial biogenesis.Keywords: anthracycline, DNA damage, mitochondrial DNA, Moringa oleifera Lam, oxidative stress