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Virus Research Sep 2023Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have...
Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 μM, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors.
Topics: Humans; COVID-19; SARS-CoV-2; Anthracyclines; Antiviral Agents
PubMed: 37379907
DOI: 10.1016/j.virusres.2023.199164 -
Molecules (Basel, Switzerland) Mar 2023Aclacinomycin A (ACM-A) is an anthracycline antitumor agent widely used in clinical practice. The current industrial production of ACM-A relies primarily on chemical... (Review)
Review
Aclacinomycin A (ACM-A) is an anthracycline antitumor agent widely used in clinical practice. The current industrial production of ACM-A relies primarily on chemical synthesis and microbial fermentation. However, chemical synthesis involves multiple reactions which give rise to high production costs and environmental pollution. Microbial fermentation is a sustainable strategy, yet the current fermentation yield is too low to satisfy market demand. Hence, strain improvement is highly desirable, and tremendous endeavors have been made to decipher biosynthesis pathways and modify key enzymes. In this review, we comprehensively describe the reported biosynthesis pathways, key enzymes, and, especially, catalytic mechanisms. In addition, we come up with strategies to uncover unknown enzymes and improve the activities of rate-limiting enzymes. Overall, this review aims to provide valuable insights for complete biosynthesis of ACM-A.
Topics: Aclarubicin; Antibiotics, Antineoplastic; Fermentation; Biosynthetic Pathways; Metabolic Engineering
PubMed: 36985733
DOI: 10.3390/molecules28062761 -
Nucleic Acids Research May 2024In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much...
In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these DNA intercalators lack the capacity to induce DNA damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that these DNA intercalators impact chromatin biology by interfering with the chromatin stability of RNA polymerases I, II and III. These three compounds have the capacity to induce degradation of RNA polymerase II and they simultaneously enable the trapping of Topoisomerases TOP2A and TOP2B on the chromatin. In addition, BMH-21 also acts as a catalytic inhibitor of Topoisomerase II, resembling Aclarubicin. Moreover, BMH-21 induces chromatin trapping of the histone chaperone FACT and propels accumulation of Z-DNA and histone eviction, similarly to Aclarubicin and CBL0137. These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.
Topics: Humans; Antigens, Neoplasm; Carbazoles; Chromatin; Diketopiperazines; DNA; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; High Mobility Group Proteins; Histones; Intercalating Agents; Poly-ADP-Ribose Binding Proteins; RNA Polymerase I; RNA Polymerase II; RNA Polymerase III; Topoisomerase II Inhibitors; Transcription, Genetic; Transcriptional Elongation Factors; Aclarubicin
PubMed: 38340348
DOI: 10.1093/nar/gkae069 -
Journal of Inorganic Biochemistry Apr 2022Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2...
Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
Topics: Anthracyclines; Arachidonic Acid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Humans; Molecular Dynamics Simulation; Myocytes, Cardiac; Protein Binding; Static Electricity
PubMed: 35078036
DOI: 10.1016/j.jinorgbio.2022.111722 -
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 -
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 -
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 -
Oxidative Medicine and Cellular... 2022The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens...
OBJECTIVE
The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro.
METHODS
We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease-free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK-8 assay. Furthermore, CCK-8 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA-mediated death pathways in AML cells. The pathway of HCA-mediated AML cell death was further verified by Hoechst/PI staining, flow cytometry, and Western blotting.
RESULTS
After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow-up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA-mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase-3, and caspase-8 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl-2 was downregulated. The expression of apoptosis-related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis-related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated.
CONCLUSIONS
HCA, as a new regimen of conventional drugs, was a safe and efficacious reinduction salvage strategy in children with refractory AML before HSCT. HCA exhibits the synergistic growth inhibition of AML cells and induces cell death mainly through apoptosis.
Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Child; Cladribine; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Retrospective Studies
PubMed: 35873796
DOI: 10.1155/2022/8212286 -
The FEBS Journal Nov 2021The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic... (Review)
Review
The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.
Topics: Aclarubicin; Antineoplastic Agents; DNA Breaks, Double-Stranded; DNA Damage; Doxorubicin; Humans
PubMed: 33022843
DOI: 10.1111/febs.15583 -
Frontiers in Oncology 2022The 7 + 3 regimen is the front-line induction chemotherapy in patients with newly diagnosed acute myeloid leukemia, with a response rate of 60-80%. But it's not suitable...
The 7 + 3 regimen is the front-line induction chemotherapy in patients with newly diagnosed acute myeloid leukemia, with a response rate of 60-80%. But it's not suitable for all patients especially old/unfit patients because of a higher treatment related toxicity. Therefore, safer and more effective induction therapies are required. In this retrospective study, 50 patients with newly diagnosed acute myeloid leukemia received decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) as induction chemotherapy. Complete remission (CR) rate was 96% (48/50) and overall response rate was 100%. Of note, All 7 patients harboring mutation achieved CR. The median overall survival (OS) was 40.0 months (range 2.0, 58.0). The OS at 1, 3, and 5 years were 75.3%, 54.2%, and 49.3%. The median relapse free survival (RFS) was 38.0 months (range 2.0, 58.0). The RFS at 1, 3, and 5 years were 67.3%, 48.9%, and 45.1%. The OS and RFS of patients who received hematopoietic stem cell transplantation (HSCT) were significantly higher than those who did not undergo HSCT (=0.017; 0.016). The incidence of grade 3-4 neutropenia and thrombocytopenia was 84% and 88%. Meanwhile, the incidence of grade 3-4 infection and bleeding was only 16% and 6%. There was no early death. In conclusion, DAC+HAAG regimen is effective and well-tolerated as induction therapy in patients with newly diagnosed AML.
PubMed: 36313659
DOI: 10.3389/fonc.2022.998884