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Biological & Pharmaceutical Bulletin Oct 2006Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor...
Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay system using a stable transformant of mammalian cells that express the luciferase reporter gene construct containing a HIF-1 binding site. Using this system, we screened 5000 cultured broths of microorganisms, and we found that cinerubin (1-hydroxy aclacinomycin B) showed a significant inhibition of the reporter activity induced by hypoxic conditions. In addition, we demonstrated that aclarubicin also inhibited the HIF-1 transcriptional activity under hypoxic conditions, but neither doxorubicin nor daunorubicin inhibited it. Consistent with these results, cinerubin and aclarubicin inhibited the hypoxic induction of the vascular endothelial growth factor (VEGF) protein in HepG2 cells, but neither doxorubicin nor daunorubicin affected it. Thus, our results suggested that some anthracyclines are also acting as angiogenesis inhibitors.
Topics: Animals; Anthracyclines; CHO Cells; Cricetinae; Hypoxia-Inducible Factor 1, alpha Subunit; Promoter Regions, Genetic; RNA, Messenger; Vascular Endothelial Growth Factor A
PubMed: 17015940
DOI: 10.1248/bpb.29.1999 -
Molecular and Clinical Oncology Dec 2021Hematopoietic stem cell transplantation (HSCT) is generally considered as the only effective treatment for children with relapsed/refractory (R/R) acute myeloid leukemia...
Hematopoietic stem cell transplantation (HSCT) is generally considered as the only effective treatment for children with relapsed/refractory (R/R) acute myeloid leukemia (AML). Achieving remission prior to HSCT affects the efficacy of the procedure and patient survival; therefore, induction therapy in children with R/R AML prior to HSCT is very important. The aim of the present study was to evaluate the clinical efficacy, prognosis and safety of 5-aza-2-deoxycytidine (DAC) combined with homoharringtonine + cytarabine + aclarubicin (HAA regimen) in the treatment of pediatric R/R AML. A total of 53 pediatric patients with R/R AML, aged 1-14 years, were treated with DAC-HAA. The overall response rate was 83.1%, with a complete remission rate of 77.4% and a partial remission rate of 5.7%. In conclusion, DAC-HAA therapy for children with R/R AML was found to be associated with a high remission rate, a short period of bone marrow suppression and a good safety profile. Therefore, DAC-HAA may be of value as a transitional regimen prior to HSCT and is worthy of clinical consideration.
PubMed: 34790353
DOI: 10.3892/mco.2021.2431 -
British Journal of Cancer Jun 1995Daunorubicin (DNR) is a major front-line drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Previously, we showed that in vitro resistance to DNR at... (Comparative Study)
Comparative Study
Daunorubicin (DNR) is a major front-line drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Previously, we showed that in vitro resistance to DNR at diagnosis is related to a poor long-term clinical outcome in childhood ALL and that relapsed ALL samples are more resistant to DNR than untreated ALL samples. In cell line studies, idarubicin (IDR), aclarubicin (ACR) and mitoxantrone (MIT) showed a (partial) lack of cross-resistance to the conventional anthracyclines DNR and doxorubicin (DOX), but clinical studies in childhood ALL have been inconclusive about the suggested lack of cross-resistance. In the present study we determined the in vitro cross-resistance pattern between DNR, DOX, IDR, ACR and MIT in 48 untreated and 39 relapsed samples from children with ALL using the MTT assay. The relapsed ALL group was about twice as resistant to DNR, DOX, IDR, ACR and MTT as the untreated ALL group. Thus, resistance developed to all five drugs. We found a significant cross-resistance between DNR, DOX, IDR, ACR and MIT, although in some individual cases in vitro anthracycline cross-resistance was less pronounced. We conclude that IDR, ACR and MIT cannot circumvent in vitro resistance to DNR in childhood ALL. Clinical studies may still prove whether IDR, ACR or MIT has a more favourable toxicity profile than DNR.
Topics: Aclarubicin; Antibiotics, Antineoplastic; Bone Marrow; Child; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Humans; Idarubicin; Mitoxantrone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 7779709
DOI: 10.1038/bjc.1995.231 -
The Journal of Antibiotics Jul 1980An aclacinomycin A-resistant subline of mouse lymphoblastoma L5178Y cells was isolated by successive treatment of tumor-bearing mice with the antibiotic. IC50 (50%...
An aclacinomycin A-resistant subline of mouse lymphoblastoma L5178Y cells was isolated by successive treatment of tumor-bearing mice with the antibiotic. IC50 (50% growth inhibition) in culture was observed at a drug concentration of 0.22 micrograms/ml, which was ca. 11 times higher than IC50 for the parental cells. The resistant cell line exhibited cross resistance to mitomycin C, actinomycin D, macromomycin, auromomycin, vinblastine, cytochalasin B, and other anthracyclines: daunorubicin, adriamycin, 4'-O-tetrahydropyranyladriamycin, baumycins A1 and A2, aclacinomycins B and Y, MA144-S1, 1-deoxypyrromycin, cinerubin A, musettamcyin, and pyrromycin. The 1-deoxy group of anthracyclines showed higher degree of cross resistance than the 1-hydroxy group. No significant cross resistance was found with bleomycin A2, neothramycin and blasticidin S. The resistance to aclacinomycin A and cross resistance to adriamycin were also demonstrated by the method of uridine incorporation. The accumulation or retention studies with [3H]adriamycin revealed that the resistance may be due to decreased uptake and increased efflux of the antibiotic in the resistant cells.
Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cell Line; Doxorubicin; Drug Resistance; Kinetics; Leukemia L5178; Leukemia, Experimental; Mice; Mice, Inbred Strains; Naphthacenes; RNA, Neoplasm
PubMed: 6931828
DOI: 10.7164/antibiotics.33.737 -
Blood Apr 1996Anthracycline antitumor drugs such as aclacinomycin (ACM) and doxorubicin (DOX) used in subtoxic concentrations induce erythroid differentiation of the erythroleukemic...
Anthracycline antitumor drugs such as aclacinomycin (ACM) and doxorubicin (DOX) used in subtoxic concentrations induce erythroid differentiation of the erythroleukemic cell line K562. To elucidate the possible role of erythroid genes of the erythropoietin receptor (EpoR) and the transcription factor GATA-1 in this effect, the regulatory regions of the above genes and human epsilon- and gamma-globin and porphobilinogen deaminase (PBGD) genes were fused to the firefly luciferase gene. The resulting reporter constructs were tested in a transfection assay of the erythroleukemic cell line K562 stimulated to differentiate by treatment with the anthracycline drugs ACM and DOX or hemin (HEM). The results showed activation of the tested promoters after cell treatment with ACM, but not with DOX or HEM. In contrast to the mouse EpoR gene promoter, the activity of the human EpoR gene promoter (-659/-60) in the reporter construct was not modified by addition of the first intron sequence. In ACM-treated K562 cells, EpoR gene promoter activity completely correlated with EpoR and GATA-1 mRNA levels and the degree of erythroid maturation. In addition, ACM strongly activated the erythroid gene promoters that contain GATA binding sites. Nevertheless, less activation was also observed for the GATA-1 gene promoter (-312/-31) lacking any known GATA binding sites. Insertion of the GATA-1 gene enhancer with two canonic GATA binding sites, stimulated the ACM activation effect for EpoR and GATA-1 promoter-containing constructs. Mutation of the enhancer GATA binding sites abolished this effect. All the regulatory regions tested (except gamma-globin promoter) were completely inactive in nonerythroid COS7 cells. These data indicate that (1) two structurally different anthracycline analogues, DOX and ACM, differ in their differentiation mechanisms, and (2) ACM switches on the erythroid program of K562 cells, at least in part because of interaction with a factor(s) that recognizes the GATA binding sites in the promoter region of erythroid genes leading to their activation.
Topics: Aclarubicin; Antibiotics, Antineoplastic; Base Sequence; Cell Differentiation; Doxorubicin; Erythropoiesis; Humans; Leukemia, Erythroblastic, Acute; Molecular Sequence Data; Promoter Regions, Genetic; Tumor Cells, Cultured
PubMed: 8639908
DOI: No ID Found -
OncoTargets and Therapy 2018Relapsed and refractory acute myeloid leukemia (RR-AML) still poses major treatment concerns. Current treatments include high doses of cytarabine or fludarabine in...
Low-dose hypomethylating agent decitabine in combination with aclacinomycin and cytarabine achieves a better outcome than standard FLAG chemotherapy in refractory/relapsed acute myeloid leukemia patients with poor-risk cytogenetics and mutations.
BACKGROUND
Relapsed and refractory acute myeloid leukemia (RR-AML) still poses major treatment concerns. Current treatments include high doses of cytarabine or fludarabine in combination with cytarabine and G-CSF (FLAG), but provide mixed results. Low-dose decitabine, a hypomethylating drug, in combination with aclarubicin and cytarabine (DAC) has shown safety and efficacy in the treatment of AML; however, clinical data are limited for the treatment of RR-AML.
METHODS
In this study, we retrospectively compared the response and safety of DAC vs FLAG for RR-AML patients.
RESULTS
For the 35 patients with RR-AML enrolled in this study, the overall response rates reached 100% and 55.6% in the DAC group and FLAG group, respectively (=0.002). Complete response rates after DAC and FLAG treatment were 64.7% and 33.3%, respectively (=0.002). Median overall survival (95% CI) of the DAC treatment group was significantly higher than for the FLAG group (median not achieved vs 16.8 months, =0.021).
CONCLUSION
DAC treatment was also more effective in those patients with poor prognosis, suggesting that DAC resulted in a better outcome for RR-AML treatment. In conclusion, in our study, DAC therapy provided more safety and effectiveness and lower toxicity in the treatment of RR-AML compared to FLAG therapy.
PubMed: 30349319
DOI: 10.2147/OTT.S161919 -
Dose-response : a Publication of... 2021We previously showed that hormetic responses can be established in cell activity tests using human and murine adherent cells. This time, we examined whether hormetic...
BACKGROUND
We previously showed that hormetic responses can be established in cell activity tests using human and murine adherent cells. This time, we examined whether hormetic responses can be established in cell proliferation tests using suspended human and murine lymphoid cells.
METHODS
Human lymphoblastoid cells (TK6) and mouse lymphoma cells (L5178Y) were cultured in multi-well culture plates and treated with mitomycin C, ethyl methansulfonate, hygromycin B, aclarubicin or colchicine at various dose levels and the number of cells was measured at varied times using a flow cytometer.
RESULTS
When the ratio of the number of cells treated with a test chemical to those in the negative control was plotted, the dose-response relationship typically showed a reverse U-shaped curve, indicating the occurrence of hormesis and existence of thresholds in cell toxicity. The hormetic responses depended largely on the test chemical, dose level and exposure time. When examining responses over the course of time, a J-shaped or fallen S-shaped curve was also observed.
CONCLUSIONS
The dose-response relationship showed a reverse U-shaped curve, a hallmark of hormesis, at least some time points for all chemicals tested here, indicating that chemical hormesis can be established in in vitro cell proliferation tests.
PubMed: 34262412
DOI: 10.1177/15593258211028473 -
Scientific Reports Oct 2020In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of...
In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CL) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CL inhibitor and the availability of the X-ray crystal structure of 3CL (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CL inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CL inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CL inhibitors. We recommend further experimental investigation of these compounds.
Topics: Aclarubicin; Aminoisobutyric Acids; Betacoronavirus; Binding Sites; COVID-19; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Databases, Factual; Humans; Hydrogen Bonding; Leucine; Molecular Docking Simulation; Molecular Dynamics Simulation; Oligopeptides; Pandemics; Pneumonia, Viral; Proline; Protease Inhibitors; Quinolines; SARS-CoV-2; Thermodynamics; Thiazoles; Viral Nonstructural Proteins
PubMed: 33077821
DOI: 10.1038/s41598-020-74468-0 -
British Journal of Cancer Dec 1996Drug resistance is a major obstacle to successful chemotherapy of primary liver cancer, which is associated with high expression of the multidrug resistance (MDR) gene... (Comparative Study)
Comparative Study
Drug resistance is a major obstacle to successful chemotherapy of primary liver cancer, which is associated with high expression of the multidrug resistance (MDR) gene product P-glycoprotein (Pgp), a multidrug efflux transporter. The most effective single agents in treatment of primary liver carcinoma belong to the anthracycline family, yet several anthracyclines are known to be substrates for Pgp. In the present study, we compared four anthracyclines with respect to cell growth inhibition, intracellular accumulation and cellular efflux using the HB8065/R human hepatoma cell line which is rich in Pgp, and the Pgp-poor parental line HB8065/S. The anthracyclines were also administered in conjunction with the Pgp-modifying agents verapamil and SDZ PSC 833 to assess modulation of resistance. The HB8065/R cells were sensitive to aclarubicin (ACL) and highly resistant to epirubicin (EPI), doxorubicin (DOX) and daunorubicin (DNR). SDZ PSC 833 enhanced accumulation, decreased efflux and increased cytotoxicity of EPI, DOX and DNR in the HB8065/R cells, but none of these effects was seen with ACL. In conclusion, ACL is apparently not transported by Pgp and retains its activity in a multidrug-resistant human hepatoma cell line; such properties can be exploited for clinical purposes.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Aclarubicin; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Cell Division; Cell Membrane; Daunorubicin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Epirubicin; Humans; Liver Neoplasms; Microscopy, Confocal; Tumor Cells, Cultured
PubMed: 8956784
DOI: 10.1038/bjc.1996.621 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Feb 2016To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed...
OBJECTIVE
To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML).
METHODS
We retrospectively analyzed 64 patients with refractory/relapsed AML who received the HAA regimen as salvage chemotherapy. The complete remission (CR)rate was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test.
RESULTS
The overall CR rate was 70.1%, and 67.1% of the patients attained CR after the first induction course. The early death rate was 0. The median follow-up time was 61 (range:6-120) months. The estimated 3-year OS rate was 46.8% and the estimated 3-year RFS rate was 42.8%. The CR rates of patients with favorable/intermediate and unfavorable cytogenetics were 76.4% and 33.3%, respectively. The 3-year OS of favorable/intermediate and unfavorable group were 53.7% and 10.0%, respectively. The median survival time of unfavorable group was only 8 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection.
CONCLUSION
HAA regimen is associated with a higher rate of CR and longer-term survival and its toxicity can be tolerated. The regimen is suitable for refractory/relapsed AML patients with favorable or intermediate risk .
Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Recurrence; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Rate
PubMed: 27014977
DOI: 10.3760/cma.j.issn.0253-2727.2016.02.003