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Science Advances Jun 2023Anthracyclines are a class of widely prescribed anticancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the...
Anthracyclines are a class of widely prescribed anticancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we used Cleavage Under Targets and Tagmentation (CUT&Tag) to profile RNA polymerase II during anthracycline treatment in cells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation affect chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of noncanonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the cancer-killing activity of aclarubicin is driven by the disruption of nucleosomes and RNA polymerase II.
Topics: Animals; Aclarubicin; RNA Polymerase II; Anthracyclines; Chromatin; Nucleosomes; Drosophila; Polyketides
PubMed: 37315134
DOI: 10.1126/sciadv.adg3257 -
European Journal of Haematology.... 1987
Clinical Trial Comparative Study Review
Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; Heart; Humans; Leukemia; Naphthacenes
PubMed: 3552719
DOI: 10.1111/j.1600-0609.1987.tb00019.x -
Anti-cancer Drugs Aug 2022Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options....
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options. Therefore, it is imperative to find novel treatment options for PDAC. Here, we tested a series of conventional chemotherapeutics together with anthracycline compounds as single agents or in combination, determining their effectivity against established commercial and patient-derived, low-passage PDAC cell lines. Proliferation and colony formation assays were performed to determine the anticancer activity of anthracyclines; aclarubicin and doxorubicin, on commercial and patient-derived, low-passage PDAC cell lines. In addition, the effect of standard-of-care drugs gemcitabine and individual components of FOLFIRINOX were also investigated. To evaluate which mechanisms of cell death were involved in drug response, cleavage of poly(ADP-ribose)polymerase was evaluated by western blot. Aclarubicin showed superior antitumor activity compared to other anthracyclines and standard of care drugs (gemcitabine and individual components of FOLFIRINOX) in a patient-derived, low-passage PDAC cell line and in commercial cell lines. Importantly, the combination of gemcitabine and aclarubicin showed a synergistic effect at a dose range where the single agents by themselves were ineffective. In parallel, evaluation of the antitumor activity of aclarubicin demonstrated an apoptotic effect in all PDAC cell lines. Aclarubicin is cytotoxic for commercial and patient-derived low-passage PDAC cell lines, at doses lower than peak serum concentrations for patient treatment. Our findings support a (re)consideration of aclarubicin as a backbone of new combination regimens for pancreatic cancer patients.
Topics: Aclarubicin; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cytotoxins; Humans; Pancreatic Neoplasms
PubMed: 35324522
DOI: 10.1097/CAD.0000000000001283 -
Journal of Medicinal Chemistry Nov 2020Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related...
Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure-function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase IIα in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing ,-dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.
Topics: Aclarubicin; Anthracyclines; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; DNA Breaks, Double-Stranded; DNA Topoisomerases, Type II; Doxorubicin; Drug Screening Assays, Antitumor; Histones; Humans; Polysaccharides; Structure-Activity Relationship
PubMed: 33064004
DOI: 10.1021/acs.jmedchem.0c01191 -
Journal of Hematology & Oncology Nov 2011The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome... (Meta-Analysis)
Meta-Analysis Review
The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995 and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis. The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one (29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In conclusion, CAG regimen was an effective and safe regimen for the treatment of AML, and may be more effective than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety in comparison with the current standard treatment.
Topics: Aclarubicin; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome; Young Adult
PubMed: 22082134
DOI: 10.1186/1756-8722-4-46 -
Gematologiia I Transfuziologiia Aug 1989
Review
Topics: Aclarubicin; Adult; Aged; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission Induction
PubMed: 2684734
DOI: No ID Found -
Annals of Hematology Jan 2016
Review
Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Combined Modality Therapy; Cytarabine; Decitabine; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Young Adult
PubMed: 26382274
DOI: 10.1007/s00277-015-2505-x -
Nature Reviews. Cancer Jun 2013
Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Doxorubicin; Nucleosomes; Promoter Regions, Genetic
PubMed: 23615693
DOI: 10.1038/nrc3528 -
Toxicology in Vitro : An International... Mar 2019In the study, the cytotoxicity and genotoxicity of aclarubicin (ACL) against A549 (human non-small cell lung adenocarcinoma) and HepG2 (human hepatocellular carcinoma)...
Aclarubicin in subtoxic doses reduces doxorubicin cytotoxicity in human non-small cell lung adenocarcinoma (A549) and human hepatocellular carcinoma (HepG2) cells by decreasing DNA damage.
In the study, the cytotoxicity and genotoxicity of aclarubicin (ACL) against A549 (human non-small cell lung adenocarcinoma) and HepG2 (human hepatocellular carcinoma) cell lines were evaluated and compared with that of doxorubicin (DOX). The effect of both anthracyclines in combination was also investigated. In order to get a deeper insight into the effectiveness of the drugs and their combination, their effects on the DNA damage and distribution of the cell cycle of A549 and HepG2 cells were investigated. After treatment with investigated compounds, apoptotic and necrotic morphological changes were estimated by double staining cells with orange acridine and ethidium bromide. The results showed that ACL was much more cytotoxic against lung (A549) and liver (HepG2) cancer cell lines than DOX. However, the drugs affected the cell cycle differently. ACL arrested cells in the G1 phase, while DOX arrested them in the G2/M phase. DOX and ACL at high concentrations are able to trigger apoptosis in both A549 and HepG2 cells. When the drugs were used in combination, subtoxic concentrations of ACL antagonized the cytotoxic effects of doxorubicin. Pre-incubation of cells with subtoxic concentrations of ACL reduced the level of DNA damage by DOX but increased DOX genotoxicity in the presence of verapamil.
Topics: A549 Cells; Aclarubicin; Antibiotics, Antineoplastic; Cell Cycle; Cell Survival; DNA Damage; Doxorubicin; Hep G2 Cells; Humans
PubMed: 30579959
DOI: 10.1016/j.tiv.2018.12.015 -
Cancer Medicine Nov 2016Homoharringtonine combined with aclarubicin and cytarabine (HAA) is a highly effective treatment for acute myeloid leukemia (AML), especially for t(8;21) AML. However,...
Homoharringtonine combined with aclarubicin and cytarabine synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein.
Homoharringtonine combined with aclarubicin and cytarabine (HAA) is a highly effective treatment for acute myeloid leukemia (AML), especially for t(8;21) AML. However, the underlying mechanisms by which HAA kills t(8;21) AML cells remain unclear. In this study, SKNO-1 and Kasumi-1 cells with t(8;21) were used. Compared with individual or pairwise administration of homoharringtonine, aclarubicin, or cytarabine, HAA showed the strongest inhibition of growth and induction of apoptosis in SKNO-1 and Kasumi-1 cells. HAA caused cleavage of the AML1-ETO (AE) oncoprotein to form truncated AE (ΔAE). Pretreatment with the caspase-3 inhibitor caspase-3 inhibitor Q-DEVD-OPh (QDO) not only suppressed HAA-induced apoptosis but also abrogated the cleavage of AE and generation of ΔAE. These results suggest that HAA synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein, thus providing direct evidence for the strong activity of HAA toward t(8;21) AML.
Topics: Aclarubicin; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit; Cytarabine; Drug Synergism; Harringtonines; Homoharringtonine; Humans; Leukemia; Oncogene Proteins, Fusion; Proteolysis; RUNX1 Translocation Partner 1 Protein; Translocation, Genetic
PubMed: 27709797
DOI: 10.1002/cam4.913