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RSC Advances Sep 2019Aclarubicin (ACR), an anthracycline anti-tumor agent, is known to play important roles in cancer. Evidence has suggested that ACR has therapeutic effects on rats...
Aclarubicin (ACR), an anthracycline anti-tumor agent, is known to play important roles in cancer. Evidence has suggested that ACR has therapeutic effects on rats intracranially implanted with C6 glioma cells. However, the function and mechanism of ACR in glioma cells remain elusive. In this study, we examined the effects of ACR on glioma cell growth, apoptosis, and DNA damage. Our results showed that treatment with different concentrations of ACR (1, 2, and 5 μM) markedly impeded glioma cell survival, significantly decreased cell proliferation, and increased cell apoptosis and caspase-3 activity. Furthermore, ACR treatment promoted DNA damage through phosphorylation of ATM and CHK1 in U87 and U251 cells. Treatment with ACR also increased sirtuin 1 (SIRT1) expression and inhibited phosphatidylinositol 3'-kinase (PI3K)/AKT pathway activation. Interestingly, we found that AKT overexpression reversed the effects of ACR on glioma cell survival, proliferation, apoptosis, and DNA damage. Thus, our data suggest that ACR induces apoptosis and DNA damage in U87 and U251 cells through the SIRT1/PI3K/AKT signaling pathway.
PubMed: 35529648
DOI: 10.1039/c9ra05572j -
Leukemia Research Oct 2002Aclarubicin (ACLA), which belongs to the antracycline class of antineoplasic agents, has been demonstrated as a differentiating agent for a broad range of human solid...
Aclarubicin (ACLA), which belongs to the antracycline class of antineoplasic agents, has been demonstrated as a differentiating agent for a broad range of human solid tumors and leukemia. By using dihydroethidium as a fluorescent probe, we show the ability of subtoxic (i.e. differentiating) concentration of ACLA to generate reactive oxygen species in both K562 and HL-60 leukemia cell lines. Besides, we have used a calcein-based spectrofluorimetric assay to determine the influence of ACLA treatment on the cellular labile iron pool (LIP). In both cell lines, the LIP level was markedly decreased in the presence of ACLA. Nevertheless, whereas ACLA-induced differentiation was obviously ROS-dependent, the LIP decrease was rather ROS-independent.
Topics: Aclarubicin; Antibiotics, Antineoplastic; Cell Differentiation; Fluorescent Dyes; Free Radicals; HL-60 Cells; Humans; Iron; K562 Cells; Leukemia; Reactive Oxygen Species
PubMed: 12163054
DOI: 10.1016/s0145-2126(02)00030-9 -
Cancer Medicine Aug 2020Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need....
Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge transplantation is a priority. The CAG (cytarabine, aclarubicin, and G-CSF) regimen was initially used by one group in China, showing unexpectedly promising results in 11 R/R-T-ALL patients. Here, we report the multicenter results of 41 patients who received the CAG regimen as salvage therapy. After one cycle of the CAG regimen, complete remission and partial remission were achieved in 33 (80.5%) and two (4.9%) patients, respectively. Failure to respond was observed in six patients (14.6%). Early T-cell precursor (ETP) (n = 26) and non-ETP (n = 15) patients had a similar CR rate (80.8% vs 80.0%, P = .95). Among 41 patients, allo-HSCT was successfully performed in 27 (66%) patients (22 in CR and 5 in non-CR). With a median follow-up time of 12 months, the estimated 2-year overall survival and event-free survival were 68.8% (95% CI, 47.3%-83.0%) and 56.5% (95% CI, 37.1%-71.9%), respectively. The CAG regimen was well-tolerated, and no early death occurred. Our multicenter results show that the CAG regimen is highly effective and safe, representing a novel choice for adult patients with R/R-T-ALL and providing a better bridge to transplantation.
Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Young Adult
PubMed: 32492289
DOI: 10.1002/cam4.3079 -
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 -
Frontiers in Oncology 2022Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are...
Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are considered be heterogenous among patients. However, reports of concurrent LCH and AML are rare. Herein we report a novel case of concurrent LCH and AML which shared same the driver mutations, strongly suggesting a common clonal origin.An 84-year-old female presented with cervical lymphadenopathy and pruritic skin rash on the face and scalp. Laboratory tests revealed pancytopenia with 13% of blasts, elevated LDH and liver enzymes, in addition to generalised lymphadenopathy and splenomegaly by computed tomography. Bone marrow specimens showed massive infiltration of MPO-positive myeloblasts, whereas S-100 and CD1a positive atypical dendritic cell-like cells accounted for 10% of the atypical cells on bone marrow pathology, suggesting a mixture of LCH and AML. A biopsy specimen from a cervical lymph node and the skin demonstrated the accumulation of atypical cells which were positive for S-100 and CD1a. LCH was found in lymph nodes, skin and bone marrow; AML was found in peripheral blood and bone marrow (AML was predominant compared with LCH in the bone marrow). Next generation sequencing revealed four somatic driver mutations (-G13D, -R140Q, and -F640fs/-I715fs), equally shared by both the lymph node and bone marrow, suggesting a common clonal origin for the concurrent LCH and AML. Prednisolone and vinblastine were initially given with partial response in LCH; peripheral blood blasts also disappeared for 3 months. Salvage chemotherapy with low dose cytarabine and aclarubicin were given for relapse, with partial response in both LCH and AML. She died from pneumonia and septicemia on day 384. Our case demonstrates a common cell of origin for LCH and AML with a common genetic mutation, providing evidence to support the proposal to classify histiocytosis, including LCH, as a myeloid/myeloproliferative malignancy.
PubMed: 36185232
DOI: 10.3389/fonc.2022.974307 -
Oncology Letters Sep 2018The low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) (CAG) priming regimen is an effective treatment for patients with relapsed or...
The low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) (CAG) priming regimen is an effective treatment for patients with relapsed or refractory acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS). G-CSF influences the bone marrow microenvironment (BMM) by mobilizing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as by reducing the expression of stromal cell-derived factor-1α (SDF-1α). In the present study, a WEHI-3-grafted BALB/c mouse AML model (AML-M4) was employed to determine how the BMM was altered by different treatment regimens. It was evident that CAG regimen decreased and increased the proportion of Tregs and MDSCs in the bone marrow and spleen, respectively. Furthermore, the CAG regimen downregulated SDF-1α levels in the bone marrow and peripheral blood. However, hematoxylin and eosin staining of the main organs revealed that leukemic cells infiltrated the liver following treatment with the CAG regimen. The present study indicates that the CAG regimen has a positive effect on the immunosuppressive microenvironment in AML and relieves AML-associated BMM immune suppression by decreasing Tregs and MDSCs in the bone marrow and downregulating the SDF-1α/CXCR4 axis in the bone marrow and peripheral blood.
PubMed: 30127892
DOI: 10.3892/ol.2018.9018 -
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 -
Anti-cancer Drugs Jan 2022Some previous researches raised the possibility of a novel acute myeloid leukemia (AML) entity presenting cup-like cytomorphology with mutations of both FLT3 and NPM1 or...
Acute myeloid leukemia with cup-like blasts and FLT3-ITD and NPM1 mutations mimics features of acute promyelocytic leukemia: a case of durable remission after sorafenib and low-dose cytarabine.
Some previous researches raised the possibility of a novel acute myeloid leukemia (AML) entity presenting cup-like cytomorphology with mutations of both FLT3 and NPM1 or one of them. However, the clinical implications of this subtype remain unknown. We describe a 63-year-old patient belonging to this distinct AML subtype, who presented similar features of acute promyelocytic leukemia (APL) including nuclear morphology, negative for CD34 and HLA-DR, and abnormal coagulation. He had no response to both arsenic trioxide and CAG regimen (cytarabine, aclarubicin, and G-CSF). Given that the patient carried the FLT3-ITD mutation, we switched to a pilot treatment of FLT3 inhibitor sorafenib combined with low-dose cytarabine (LDAC). To date, the patient achieved durable complete remission over 58 months. These findings suggest that AML with cup-like blasts and FLT3-ITD and NPM1 mutations mimic APL, and the prognosis of this subtype may be improved by sorafenib combined with LDAC.
Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; HLA-DR Antigens; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Nucleophosmin; Sorafenib; fms-Like Tyrosine Kinase 3
PubMed: 34459465
DOI: 10.1097/CAD.0000000000001228 -
Journal of Translational Medicine Jul 2019The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug...
BACKGROUND
The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations.
METHODS
DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed.
RESULTS
DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035).
CONCLUSION
Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.
Topics: Adolescent; Adult; Aged; Alleles; Anthracyclines; Asian People; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Prognosis; Proportional Hazards Models; Young Adult
PubMed: 31291961
DOI: 10.1186/s12967-019-1959-3 -
Journal of Oncology 2022Homoharringtonine- (HHT-) based HHT, aclarubicin, and cytarabine (HAA) induction regimen is the first-line therapy for nonelder acute myeloid leukemia (AML) patients in...
Homoharringtonine- (HHT-) based HHT, aclarubicin, and cytarabine (HAA) induction regimen is the first-line therapy for nonelder acute myeloid leukemia (AML) patients in China. However, drug resistance is a new challenge, and little attention has been devoted to excavating resistant mechanisms. This study used the classic method to construct six HHT-resistant cell lines with a gradually increasing resistance index (RI) to discover HHT drug resistance mechanisms dynamically. After HHT resistance, the cell growth rate decreased, cell cycle delayed, and P-glycoprotein (p-gp, CD243) expression levels increased. Furthermore, we explored the changes in transcriptomics between HHT-sensitive and HHT-resistant cells using RNA-sequence. Through Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and hub gene analyses, we found that immune activity, especially G-protein coupled receptor (GPR) and related molecules, may mediate HHT resistance. Moreover, Calcitonin Receptor-Like (CALCRL) and Protein Subunit Alpha I1 (GNAI1), which belong to GPRs, were stimulated in HHT-resistant cell strains in vitro and vivo, indicating that they may play a critical role in HHT resistance. In addition, these two genes have prognostic significance for AML patients. Taken together, we successfully constructed HHT-resistant cell lines with dynamic RIs and explored the resistance mechanisms, which will help identify new drugs for HHT-resistant AML patients.
PubMed: 36081671
DOI: 10.1155/2022/2813938