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1.
Int J Radiat Oncol Biol Phys ; 85(5): e239-48, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23332223

ABSTRACT

PURPOSE: To investigate possible radiosensitizing activities of the well-known peroxisome proliferator-activated receptor (PPAR)γ ligand ciglitazone and novel PPARγ ligands CAY10415 and CAY10506 in non-small cell lung cancer (NSCLC) cells. METHODS AND MATERIALS: Radiosensitivity was assessed using a clonogenic cell survival assay. To investigate the mechanism underlying PPARγ ligand-induced radiosensitization, the subdiploid cellular DNA fraction was analyzed by flow cytometry. Activation of the caspase pathway by combined PPARγ ligands and γ-radiation treatment was detected by immunoblot analysis. Reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry. RESULTS: The 3 PPARγ ligands induced cell death and ROS generation in a PPARγ-independent manner, enhanced γ-radiation-induced apoptosis and caspase-3-mediated poly (ADP-ribose) polymerase (PARP) cleavage in vitro. The combined PPARγ ligand/γ-radiation treatment triggered caspase-8 activation, and this initiator caspase played an important role in the combination-induced apoptosis. Peroxisome proliferator-activated receptor-γ ligands may enhance the γ-radiation-induced DNA damage response, possibly by increasing γ-H2AX expression. Moreover, the combination treatment significantly increased ROS generation, and the ROS scavenger N-acetylcysteine inhibited the combined treatment-induced ROS generation and apoptotic cell death. CONCLUSIONS: Taken together, these results indicated that the combined treatment of PPARγ ligands and γ-radiation synergistically induced DNA damage and apoptosis, which was regulated by ROS.


Subject(s)
Apoptosis , Carcinoma, Non-Small-Cell Lung/therapy , DNA Damage , Lung Neoplasms/therapy , PPAR gamma/metabolism , Radiation Tolerance/drug effects , Reactive Oxygen Species/metabolism , Thiazolidinediones/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Caspase 3/metabolism , Caspase 8/metabolism , Fluoresceins , Gamma Rays/therapeutic use , Histones/metabolism , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Peroxisome Proliferator-Activated Receptors , Poly(ADP-ribose) Polymerases/metabolism , Radiation Tolerance/physiology , Tumor Stem Cell Assay/methods
2.
Apoptosis ; 17(2): 200-16, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22002103

ABSTRACT

In the present study, we investigated the signaling pathways implicated in the induction of apoptosis by two modified nucleosides, 5-phenylselenyl-methyl-2'-deoxyuridine (PhSe-T) and 5-methylselenyl-methyl-2'-deoxyuridine (MeSe-T), using human cancer cell lines. The induction of apoptosis was associated with proteolytic activation of caspase-3 and -9, PARP cleavage, and decreased levels of IAP family members, including c-IAP-1 and c-IAP-2, but had no effect on XIAP and survivin. PhSe-T and MeSe-T also enhanced the activities of caspase-2 and -8, Bid cleavage, and the conformational activation of Bax. Additionally, nucleoside derivative-induced apoptosis was inhibited by the selective inhibitors of caspase-2, -3, -8, and -9 and also by si-RNAs against caspase-2, -3, -8, and -9; however, inhibition of caspase-2 and -3 was more effective at preventing apoptosis than inhibition of caspase-8 and -9. Moreover, the inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk or by the knockdown of protein expression using siRNA suppressed nucleoside derivative-induced caspase-3 activation, but not vice versa. PhSe-T and MeSe-T also induced a Δψ(m) loss via a CsA-insensitive mechanism, ROS production, and DNA damage, including strand breaks. Moreover, ROS scavengers such as NAC, tiron, and quercetin inhibited nucleoside derivative-induced ROS generation and apoptosis by blocking the sequential activation of caspase-2 and -3, indicating the role of ROS in caspase-2-mediated apoptosis. Taken together, these results indicate that caspase-2 acts upstream of caspase-3 and that caspase-2 functions in response to DNA damage in both PhSe-T- and MeSe-T-induced apoptosis. Our results also suggest that ROS are critical regulators of the sequential activation of caspase-2 and -3 in nucleoside derivative-treated cancer cells.


Subject(s)
Apoptosis/drug effects , Caspase 2/metabolism , Caspase 3/metabolism , Deoxyuridine/analogs & derivatives , Neoplasms/metabolism , Organoselenium Compounds/administration & dosage , Apoptosis/genetics , Caspase 2/genetics , Caspase 3/genetics , Caspase Inhibitors , Cell Line, Tumor , DNA Damage/drug effects , Deoxyuridine/administration & dosage , Enzyme Activation/drug effects , Humans , Oligopeptides/administration & dosage , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction
3.
Biol Blood Marrow Transplant ; 18(6): 944-50, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22155501

ABSTRACT

Busulfan has a narrow therapeutic range, and in children, pharmacokinetic variability has been found to be high even after the use of intravenous (i.v.) busulfan. Recently, a reduced toxicity myeloablative regimen showed promising results, but the data of busulfan pharmacokinetics in hematopoietic stem cell transplantation (HSCT) using a targeted busulfan/fludarabine regimen in children has not yet been reported. We performed therapeutic drug monitoring (TDM) after once-daily i.v. busulfan combined with fludarabine and analyzed the outcomes. Busulfan (i.v.) was administered once daily for 4 consecutive days. The daily target area under the curve (AUC) was 18,125-20,000 µg*h/L/day (4415-4872 µmol*min/L/day), which was reduced to 18,000-19,000 µg*h/L/day (4384-4628 µmol*min/L/day) after a high incidence of toxicity was observed. A total of 24 patients were enrolled. After infusion of busulfan on the first day, patients showed AUC that ranged from 12,079 to 31,660 µg*h/L (2942 to 7712 µmol*min/L) (median 16,824 µg*h/L, percent coefficient of variation (%CV) = 26.5%), with clearance of 1.74-6.94 mL/min/kg (median 4.03 mL/min/kg). We performed daily TDM in 20 patients, and during the daily TDM, the actual AUC ranged from 73% to 146% of the target AUC, showing high intraindividual variability. The %CV of busulfan clearance of each individual ranged from 7.7% to 38.7%. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m(2) to 689.3 mg/m(2). Graft failure occurred in 3 patients with total AUC less than 74,000 µg*h/L (18,026 µmol*min/L), and 2 patients with relatively high total AUC experienced veno-occlusive disease. Busulfan pharmacokinetics showed high inter- and intraindividual variability in HSCT using a targeted busulfan/fludarabine regimen, which indicates the need for intensive monitoring and dose adjustment to improve the outcome of HSCT. Currently, we are performing a newly designed phase II study to decrease regimen-related toxicities and reduce graft failure by setting an optimal target AUC based on this study.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bone Marrow Transplantation , Leukemia, Myeloid, Acute/therapy , Peripheral Blood Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Area Under Curve , Busulfan/administration & dosage , Child , Child, Preschool , Drug Administration Schedule , Female , Graft vs Host Disease/prevention & control , Humans , Infant , Leukemia, Myeloid, Acute/immunology , Male , Models, Statistical , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Transplantation, Homologous , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives
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