Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- Apoptotic efficacy of etomoxir in human acute myeloid leukemia cells. Cooperation with arsenic trioxide and glycolytic inhibitors, and regulation by oxidative stress and protein kinase activities. [Journal Article]
- PLoS One 2014; 9(12):e115250.
Fatty acid synthesis and oxidation are frequently exacerbated in leukemia cells, and may therefore represent a target for therapeutic intervention. In this work we analyzed the apoptotic and chemo-sensitizing action of the fatty acid oxidation inhibitor etomoxir in human acute myeloid leukemia cells. Etomoxir caused negligible lethality at concentrations up to 100 µM, but efficaciously cooperated to cause apoptosis with the anti-leukemic agent arsenic trioxide (ATO, Trisenox), and with lower efficacy with other anti-tumour drugs (etoposide, cisplatin), in HL60 cells. Etomoxir-ATO cooperation was also observed in NB4 human acute promyelocytic cells, but not in normal (non-tumour) mitogen-stimulated human peripheral blood lymphocytes. Biochemical determinations in HL60 cells indicated that etomoxir (25-200 µM) dose-dependently inhibited mitochondrial respiration while slightly stimulating glycolysis, and only caused marginal alterations in total ATP content and adenine nucleotide pool distribution. In addition, etomoxir caused oxidative stress (increase in intracellular reactive oxygen species accumulation, decrease in reduced glutathione content), as well as pro-apoptotic LKB-1/AMPK pathway activation, all of which may in part explain the chemo-sensitizing capacity of the drug. Etomoxir also cooperated with glycolytic inhibitors (2-deoxy-D-glucose, lonidamine) to induce apoptosis in HL60 cells, but not in NB4 cells. The combined etomoxir plus 2-deoxy-D-glucose treatment did not increase oxidative stress, caused moderate decrease in net ATP content, increased the AMP/ATP ratio with concomitant drop in energy charge, and caused defensive Akt and ERK kinase activation. Apoptosis generation by etomoxir plus 2-deoxy-D-glucose was further increased by co-incubation with ATO, which is apparently explained by the capacity of ATO to attenuate Akt and ERK activation. In summary, co-treatment with etomoxir may represent an interesting strategy to increase the apoptotic efficacy of ATO and (with some limitations) 2-deoxy-D-glucose which, although clinically important anti-tumour agents, exhibit low efficacy in monotherapy.
- 5-Azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation. [JOURNAL ARTICLE]
- Int J Oncol 2014 Dec 10.
The DNA methyltransferase (DNMT) inhibitory drugs such as 5-azacytidine induce DNA hypomethylation by inhibiting DNA methyltransferases. While clinically effective, DNMT inhibitors are not curative. A combination with cytotoxic drugs might be beneficial, but this is largely unexplored. In the present study, we analyzed potential synergisms between cytotoxic drugs and 5-azacytidine in acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cells. Lung cancer and leukemia cell lines were exposed to low doses of 5-azacytidine with varying doses of cytarabine or etoposide for AML cells (U937 and HL60) as well as cisplatin or gemcitabine for NSCLC cells (A549 and HTB56) for 48 h. Drug interaction and potential synergism was analyzed according to the Chou-Talalay algorithm. Further analyses were based on soft agar colony formation assays, active caspase-3 staining and BrdU incorporation flow cytometry. To identify effects on DNA methylation patterns, we performed genome wide DNA methylation analysis using 450K bead arrays. Azacytidine at low doses was synergistic with cytotoxic drugs in NSCLC and in AML cell lines. Simultaneous exposure to 5-azacytidine with cytotoxic drugs showed strong synergistic activity. In colony formation assays these synergisms were repeatedly verified for 5-azacytidine (25 nM) with low doses of anticancer agents. 5-azacytidine neither affected the cell cycle nor increased apoptosis. 450K methylation bead arrays revealed 1,046 CpG sites in AML and 1,778 CpG sites in NSCLC cells with significant DNA hypomethylation (24-h exposure) to 5-azacytidine combined with the cytotoxic drugs. These CpG-sites were observed in the candidate tumor-suppressor genes MGMT and THRB. Additional incubation time after 24-h treatment led to a 4.1-fold increase of significant hypomethylated CpG-sites in NSCLC cells. These results suggest that the addition of DNA demethylating agents to cytotoxic anticancer drugs exhibits synergistic activity in AML and NSCLC. Dysregulation of an equilibrium of DNA methylation in cancer cells might increase the susceptibility for cytotoxic drugs.
- Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia. [Journal Article]
- Rinsho Ketsueki 2014 Nov; 55(11):2316-9.
Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required.
- Deubiquitinase OTUD5 mediates the sequential activation of PDCD5 and p53 in response to genotoxic stress. [JOURNAL ARTICLE]
- Cancer Lett 2014 Dec 8.
Programmed cell death 5 (PDCD5) positively regulates p53-mediated apoptosis and rapidly accumulates upon DNA damage. However, the underlying mechanism of PDCD5 upregulation during the DNA damage response remains unknown. Here, we found that OTU deubiquitinase 5 (OTUD5) was bound to PDCD5 in response to etoposide treatment and increased the stability of PDCD5 by mediating deubiquitination of PDCD5 at Lys-97/98. Overexpression of OTUD5 efficiently enhanced the activation of both PDCD5 and p53. Conversely, PDCD5 knockdown greatly attenuated the effect of OTUD5 on p53 activation. In addition, when OTUD5 was depleted, PDCD5 failed to facilitate p53 activation, demonstrating an essential role for the PDCD5-OTUD5 network in p53 activation. Importantly, we found that OTUD5-dependent PDCD5 stabilization was required for sequential activation of p53 in response to genotoxic stress. The sequential activation of PDCD5 and p53 was abrogated by knockdown of OTUD5. Finally, impairment of the genotoxic stress response upon PDCD5 ablation was substantially rescued by reintroducing PDCD5(WT) but not PDCD5(E94D) (defective for OTUD5 interaction) or PDCD5(E16D) (defective for p53 interaction). Together, our findings have uncovered an apoptotic signaling cascade linking PDCD5, OTUD5, and p53 during genotoxic stress responses.
- Feasibility and efficacy of simultaneous integrated boost intensity-modulated radiation therapy in patients with limited-disease small cell lung cancer. [JOURNAL ARTICLE]
- Radiat Oncol 2014 Dec 11; 9(1):280.
PurposeTo evaluate the feasibility and efficacy of simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) in patients with limited-disease small-cell lung cancer (LD-SCLC).MethodsPatients with LD-SCLC were treated with SIB-IMRT within 1 week after completion of 2 cycles of induction chemotherapy. Then 2-4 cycles of adjuvant chemotherapy were administered within 1 week after SIB-IMRT. Irradiation was given accelerated hyper-fractionated with the prescribed dose 57Gy at 1.9Gy twice daily to the gross tumor volume (GTV) , 51Gy at 1.7Gy twice daily to the clinical tumor volume (CTV) and 45Gy at 1.5Gy twice daily to the planning target volume (PTV). The chemotherapy regimen consisted of platinum plus etoposide. Prophylactic cranial radiation (25Gy in 10 fractions) was administered to patients who got complete response (CR) or near complete response (nCR). The primary endpoint of this study was the frequency of grade 3 or higher acute non-hematologic treatment-related toxicities. Secondary end points included objective response, overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS).ResultsA cohort of 35 patients were enrolled in the study, the biological equivalent dose (BED) of the GTV in the SIB-IMRT was 59.16Gy. Grade 1, 2, and 3 esophagitis were observed in 11 (31%), 12 (34%), and 6 (17%) patients, respectively; Grade 1 and 2 pneumonitis were observed in 8 (23%) and 4 (11%) patients, respectively. The median OS and PFS of the whole group were 37.7 months and 29.3 months, respectively. The 1- and 2-year OS was 94.1% and 68.5%, respectively. The 1- and 2-year PFS was 76.8% and 40.7%, respectively. The 1- and 2-year LRFS was 87.7% and 73.8%, respectively.ConclusionsSIB-IMRT was feasible and well-tolerated in patients with LD-SCLC, and worth further evaluating in a large prospective clinical trial.
- Synergistic Effect of Curcumin in Combination with Anticancer Agents in Human Retinoblastoma Cancer Cells Lines. [JOURNAL ARTICLE]
- Curr Eye Res 2014 Dec 11.:1-13.
Abstract Purpose: Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of the herb Curcuma longa, is known to have anti-proliferative and anti-tumor properties. In this study, we evaluated the cytotoxic effect of curcumin alone and in combination with individual drugs like carboplatin, etoposide, or vincristine in a human retinoblastoma (RB) cancer cell line. Materials and methods: A drug-drug interaction was analyzed using the median effect/isobologram method and combination index values were used to characterize the interaction as synergistic or additive. We also performed the apoptosis and cell-cycle kinetics study with single drugs in combination with curcumin in a human RB cell lines (Y79 and Weri-Rb1). Results: Curcumin caused concentration-dependent decrease in cell proliferation, cell kinetics, and also induced apoptosis in both the RB cell lines. When combination of curcumin with individual drugs like carboplatin or etoposide or vincristine was treated on to RB cells, both cell viability and cell cycling were reduced and increased apoptosis was noted, in comparison with single drug treatment. These effects were significant in both the cell lines, indicating the ability of curcumin to increase the sensitivity of RB cells to chemotherapy drugs. Conclusion: Our in vitro findings showed that the combination of curcumin with single drug treatment showed marked synergistic inhibitory effect against RB cell lines. These results suggest that curcumin can be used as a modulator which may have a potential therapeutic value for the treatment of RB cancer patients.
- Synthesis and Biological Evaluation of Pyrazolo[3,4-b]pyridin-4-ones as a New Class of Topoisomerase II Inhibitors. [JOURNAL ARTICLE]
- Med Chem 2014 Dec 10.
A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIβ binding sites in the DNA binding interface were performed.
- The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis. [JOURNAL ARTICLE]
- Indian J Cancer 2014 July-September; 51(3):324-329.
Background:Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor and associated with alterations in the coagulation system. Addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) had resulted in increase in survival. The present retrospective trial was designed to determine whether the duration of dalteparin usage has an effect on progression and survival. Materials and
Methods:The medical records of 67 patients with SCLC who were given cisplatin-etoposide and concomitant LMWH (dalteparin) was evaluated retrospectively.
Results:Median follow-up of patients was 11.3 months. Outcome: 10.6% complete response, 3.0% good partial response, 36.4% partial response, 10.6% stable disease, and 39.4% progressive disease. Side-effects were seen in 40.3% of the patients. Median dalteparin duration was 6,1 months. According the duration of dalteparin patients were grouped in three: who took dalteparin less than 4 months (Group A), 4-6 months (Group B) and more than 6 months (Group C). Mean overall survival (OS) in Group A was 6.5 months, in Group B 11.8 months, and Group C 14.6 months. Mean OS in Group B and C were statistically significantly (P < 0.001) longer than Group A, between Group B and C there was not any significant difference (P = 0.037). Mean progression free survival (PFS) was 9 months.
Conclusions:The CT plus LMWH minimum 4 months long is well-tolerable, and may improve PFS and OS in patients with SCLC. For treatment of patients with SCLC CT plus LMWH may be considered as effective future-therapy, and further multi-centre randomised prospective clinical trials must be done to determine the new standard treatment approach for SCLC.
- The antioxidant quercetin protects HL-60 cells with high myeloperoxidase activity against pro-oxidative and apoptotic effects of etoposide. [JOURNAL ARTICLE]
- Acta Biochim Pol 2014 Dec 11.
The protective action of quercetin against the pro-oxidant and apoptotic effect of etoposide was investigated in HL-60 cells with a high level of myeloperoxidase (MPO) activity and in cells treated with MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH). Quercetin significantly protected MPO-rich cells against the pro-oxidative (p < 0.05) and apoptotic (p < 0.05) effects of etoposide. Pre-treatment with ABAH abolished this protective influence of quercetin on apoptosis induced by etoposide but actually enhanced the action effect of quercetin against etoposide-generated reactive oxygen species (ROS) level by this cytostaic drug. Thus quercetin can protect HL-60 cells against the pro-oxidative activity of etoposides regardless of MPO activity.
- Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer. [JOURNAL ARTICLE]
- Braz J Med Biol Res 2015 Jan; 48(1):13-24.
Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.