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Cancer Pathogenesis and Therapy Apr 2024Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA)...
BACKGROUND
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML.
METHODS
This study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed.
RESULTS
The most adverse prognosis of DCAG-treated patients was observed in those with or mutations during univariable analysis, whereas mutation was solely significant in multivariable analysis, with an increased likelihood of CIR ( = 0.001) and reduced LFS duration ( = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk ( = 0.044) and decreased LFS duration ( = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range.
CONCLUSION
NGS demonstrated a dismal overall outcome in patients with the rare mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.
PubMed: 38601484
DOI: 10.1016/j.cpt.2023.10.002 -
Frontiers in Bioengineering and... 2024Daunorubicin and doxorubicin, two anthracycline polyketides produced by , are potent anticancer agents that are widely used in chemotherapy, despite severe side...
Daunorubicin and doxorubicin, two anthracycline polyketides produced by , are potent anticancer agents that are widely used in chemotherapy, despite severe side effects. Recent advances have highlighted the potential of producing improved derivatives with reduced side effects by incorporating l-rhodosamine, the -dimethyl analogue of the native amino sugar moiety. In this study, we aimed to produce -dimethylated anthracyclines by engineering the doxorubicin biosynthetic pathway in the industrial strain G001. To achieve this, we introduced genes from the aclarubicin biosynthetic pathway encoding the sugar -methyltransferases AclP and AknX2. Furthermore, the native gene for glycosyltransferase DnrS was replaced with genes encoding the aclarubicin glycosyltransferases AknS and AknT. Additionally, the gene for methylesterase RdmC from the rhodomycin biosynthetic pathway was introduced. A new host was engineered successfully, whereby genes from the aclarubicin pathway were introduced and expressed. LC-MS/MS analysis of the engineered strains showed that dimethylated sugars were efficiently produced, and that these were incorporated ino the anthracycline biosynthetic pathway to produce the novel dimethylated anthracycline -dimethyldaunorubicin. Further downstream tailoring steps catalysed by the cytochrome P450 monooxygenase DoxA exhibited limited efficacy with -dimethylated substrates. This resulted in only low production levels of -dimethyldaunorubicin and no -dimethyldoxorubicin, most likely due to the low affinity of DoxA for dimethylated substrates. G001 was engineered such as to produce -dimethylated sugars, which were incorporated into the biosynthetic pathway. This allowed the successful production of -dimethyldaunorubicin, an anticancer drug with reduced cytotoxicity. DoxA is the key enzyme that determines the efficiency of the biosynthesis of -dimethylated anthracyclines, and engineering of this enzyme will be a major step forwards towards the efficient production of more -dimethylated anthracyclines, including -dimethyldoxorubicin. This study provides valuable insights into the biosynthesis of clinically relevant daunorubicin derivatives, highlighting the importance of combinatorial biosynthesis.
PubMed: 38481571
DOI: 10.3389/fbioe.2024.1363803 -
International Journal of Infectious... May 2024We investigated the validity of claims of the healthy vaccinee effect (HVE) in COVID-vaccine studies by analyzing associations between all-cause mortality (ACM) and...
Does the healthy vaccinee bias rule them all? Association of COVID-19 vaccination status and all-cause mortality from an analysis of data from 2.2 million individual health records.
OBJECTIVES
We investigated the validity of claims of the healthy vaccinee effect (HVE) in COVID-vaccine studies by analyzing associations between all-cause mortality (ACM) and COVID-19 vaccination status.
METHODS
Approximately 2.2 million individual records from two Czech health insurance companies were retrospectively analyzed. Each age group was stratified according to the vaccination status (unvaccinated vs. individuals less than 4 weeks vs. more than 4 weeks from Doses 1, 2, 3, and 4 or more doses of vaccine). ACMs in these groups were computed and compared.
RESULTS
Consistently over datasets and age categories, ACM was substantially lower in the vaccinated than unvaccinated groups regardless of the presence or absence of a wave of COVID-19 deaths. Moreover, the ACMs in groups more than 4 weeks from Doses 1, 2, or 3 were consistently several times higher than in those less than 4 weeks from the respective dose. HVE appears to be the only plausible explanation for this, which is further corroborated by a created mathematical model.
CONCLUSIONS
In view of the presence of HVE, the baseline difference in the frailty of vaccinated and unvaccinated populations in periods without COVID-19 must be taken into account when estimating COVID-19 vaccine effectiveness from observational data.
Topics: Humans; COVID-19; COVID-19 Vaccines; Retrospective Studies; Aclarubicin; Health; Vaccination
PubMed: 38401782
DOI: 10.1016/j.ijid.2024.02.019 -
IScience Mar 2024Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following...
Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin, Aclarubicin, and Amrubicin. Doxorubicin and Aclarubicin unlike Amrubicin substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated annually.
PubMed: 38384853
DOI: 10.1016/j.isci.2024.109139 -
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 Medicinal Chemistry Aug 2023The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the...
The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure-activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in relevant human cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients.
Topics: Humans; Anthracyclines; Doxorubicin; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Chromatin; DNA; Neoplasms
PubMed: 37561481
DOI: 10.1021/acs.jmedchem.3c00853 -
OncoTargets and Therapy 2023We performed sequential molecular analyses of a 75-year-old woman with -ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At...
Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an -ITD Positive AML Patient with Long-Term Gilteritinib Therapy.
We performed sequential molecular analyses of a 75-year-old woman with -ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, -ITD, , and mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. -ITD and mutations were persistently positive, and the patient received gilteritinib therapy. Although the -ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the -ITD clone was detected again. Gilteritinib treatment was restarted, and -ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) -ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.
PubMed: 37465589
DOI: 10.2147/OTT.S417137 -
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 -
OncoTargets and Therapy 2023The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however,...
PURPOSE
The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however, few studies have been published on the efficacy and safety of VEN combined with both hypomethylating agents (HMAs) and low-dose chemotherapy for patients with unfit or R/R AML.
METHODS
This study retrospectively analyzed the clinical characteristics, treatment details, safety profile and clinical outcomes of patients with unfit or R/R AML treated with VEN+ HMAs+ half-dose CAG (LDAC, aclarubicin and granulocyte colony-stimulating factor).
RESULTS
A total of 24 AML patients were involved in the study, of whom 13 (54.2%) were in the unfit group, and 11 (45.8%) were in the R/R group. and (8/24, 33.3%) were the most common gene aberrations. Patients in the R/R group were found to be more likely to carry (5/11, 45.5%) compared with the unfit group (0/13, 0%) ( = 0.006). The ORR observed during the study was 83.3% (20/24; 14 CR, 2CRi, 4PR). In the unfit group, 11/13 (84.6%) patients achieved cCR (10 CR and 1 CRi); while 5/11 (45.5%) R/R patients achieved response (4 CR and 1 CRi). CR was observed in all AML patients with (5/5), (3/3), (3/3) and (3/3). The most common adverse events (AEs) during VEN+ HMAs+ half-dose CAG therapy were persistent cytopenias and infections.
CONCLUSION
The results of this study confirm that VEN+ HMAs+ half-dose CAG is associated with promising efficacy (even high-risk molecular patterns) and tolerable safety profile in patients with unfit or R/R AML. Yet, the study involves only a small sample size, which should not be overlooked. As such, further studies on the efficacy of VEN combined with HMAs and half-dose CAG regimen in AML patients are essential.
PubMed: 37334144
DOI: 10.2147/OTT.S405611 -
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