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Anti-cancer Agents in Medicinal... 2022Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of...
Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of global deaths and accounted for approximately 9.6 million deaths or one in six deaths in 2018. The National Cancer Registry Programme Report 2020, released by the ICMRIndia, estimated that there would be 13,90,000 cases of cancer in India in 2020 and that this number is likely to rise to 15,70,000 by 2025. In spite of several anti-cancer drugs, cancer cannot be cured completely, especially at late stages. In the current era, almost every person is suffering from some kind of disease. Thus, it is the necessity of time to develop novel, potent bioactive molecules. Many researchers are working on the development of new lead molecules or finding a new biological target for the betterment of human beings. However, heterocycles are constantly being used for the discovery of new lead molecules. Many of the clinically approved drugs contain the heterocyclic core as these molecules show exhilarating pharmaceutical properties, including anti-cancer agents such as methotrexate, vinblastine, vincristine, daunorubicin, 5-fluorouracil, doxorubicin, etc. Thus, heterocyclic compounds provide a fascinating research area for the design and development of anti-cancer drug(s). Herein, we focused on the natural as well as synthetic anti-cancer heterocyclic compounds. Furthermore, efforts have been made toward the mechanism of action of selected heterocyclic anti-cancer compounds.
Topics: Antineoplastic Agents; Daunorubicin; Doxorubicin; Fluorouracil; Heterocyclic Compounds; Humans; Methotrexate; Neoplasms; Pharmaceutical Preparations; Vinblastine; Vincristine
PubMed: 35379130
DOI: 10.2174/1871520622666220404082648 -
Biochimica Et Biophysica Acta.... Jan 2024Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding...
BACKGROUND
Acute myeloid leukemia (AML) presents ongoing therapeutic challenges due to its intricate molecular pathogenesis. This study aimed to elucidate the role of RNA binding motif protein 39 (RBM39) in AML cell proliferation, apoptosis, and chemosensitivity, and its potential modulation of the PI3K/AKT pathway.
METHODS
In vitro and in vivo experiments were conducted using AML cell lines (K562 and U937) and bone marrow mononuclear cells (BM-MNCs) from AML patients and healthy donors. RBM39 mRNA and protein levels were measured using qRT-PCR and Western blotting. Cells were transfected with sh-RBM39 or sh-control, and then treated with daunorubicin (DNR) or homoharringtonine (HHT) at varied concentrations. Cell proliferation, chemosensitivity, and apoptosis were assessed through CCK-8 assay and Annexin V-APC/PI staining. RNA sequencing identified differentially expressed genes (DEGs) post RBM39 knockdown. An in vivo xenograft AML model using E7070, a selective RBM39 inhibitor, was employed to evaluate RBM39 modulation effects.
RESULTS
Elevated RBM39 levels were found in AML patients and cell lines compared to controls. RBM39 knockdown promoted apoptosis, curtailed cell proliferation, and enhanced chemosensitivity to DNR and HHT in vitro. Drug-resistant or relapsed AML patients displayed higher RBM39 levels. RNA sequencing after RBM39 knockdown revealed downregulated PI3K/AKT signaling. The xenograft model validated in vitro results, as E7070 treatment suppressed AML xenograft growth via RBM39-mediated PI3K/AKT pathway suppression.
CONCLUSION
RBM39 plays a pivotal role in AML progression through the PI3K/AKT signaling pathway. Targeting RBM39, potentially with E7070, could inhibit proliferation and induce apoptosis in AML cells, offering a promising avenue for future AML research and treatment.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Leukemia, Myeloid, Acute; Daunorubicin
PubMed: 37852323
DOI: 10.1016/j.bbamcr.2023.119607 -
International Journal of Pharmaceutics Nov 2023As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard...
As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.
Topics: Humans; Liposomes; Copper; Daunorubicin; Leukemia, Myeloid, Acute; Cytarabine
PubMed: 37820944
DOI: 10.1016/j.ijpharm.2023.123500 -
Leukemia Jun 2022Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many...
Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.
Topics: Antineoplastic Agents; Cell Self Renewal; Daunorubicin; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Leukotriene B4; Neoplastic Stem Cells
PubMed: 35461365
DOI: 10.1038/s41375-022-01579-0 -
Blood Advances Mar 2024Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid...
Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid leukemia (AML)-type intensive and nonintensive hypomethylating agent-based regimens is not well studied. We therefore performed a retrospective analysis of patients with MPN-AP/BP (N = 138) treated with intensive (N = 81) and nonintensive (N = 57) blast-reduction strategies. We used clinically relatable response criteria developed at the Princess Margaret Cancer Centre. The overall best response, comprising complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and reversion to chronic phase MPN (cMPN), in the intensive and nonintensive groups was 77% (62 of 81) and 39% (21 of 54), respectively. Similar overall best response rates were observed in patients receiving induction with daunorubicin combined with cytarabine arabinoside (daunorubicin + ara-C) (74% [23 of 31]) or FLAG-IDA/NOVE-HiDAC (78% [39 of 50], P = .78). However, patients receiving daunorubicin + ara-C more often required second inductions (29% [9 of 31] vs 4% [2 of 50], P = .002). Most responses in the entire cohort were reversions to cMPN (55 of 83 [66%]). CR and CRi comprised 30% (25 of 83) and 4% (3 of 83) of responses, respectively. Mutations in TP53 (overall response [OR] 8.2 [95% confidence interval [CI] 2.01, 37.1], P = .004) and RAS pathway (OR 5.1 [95%CI 1.2, 23.7], P = .03) were associated with inferior treatment response for intensively treated patients, and poorer performance status (Eastern Cooperative Oncology Group) was associated with inferior treatment response in both intensively (OR 10.4 [95% CI 2.0, 78.5], P = .009) and nonintensively treated groups (OR 12 [95% CI 2.04, 230.3], P = .02). In patients with paired samples before and after therapy (N = 26), there was a significant residual mutation burden remaining irrespective of response to blast-reduction therapy.
Topics: Humans; Treatment Outcome; Retrospective Studies; Myeloproliferative Disorders; Cytarabine; Daunorubicin
PubMed: 38170760
DOI: 10.1182/bloodadvances.2023011735 -
The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Leukemia, Myeloid, Acute; Daunorubicin; Benzothiazoles; Phenylurea Compounds; Mutation
PubMed: 37871118
DOI: 10.58347/tml.2023.1687d -
Minerva Medica Oct 2020
Topics: Acute Disease; Aminopyridines; Antineoplastic Agents; Antineoplastic Agents, Immunological; Congresses as Topic; Cytarabine; Daunorubicin; Gemtuzumab; Glycine; Humans; Leukemia; Pyridines; Recombinant Fusion Proteins; Staurosporine; Triazines; fms-Like Tyrosine Kinase 3
PubMed: 32957743
DOI: 10.23736/S0026-4806.20.07049-4 -
International Journal of Nanomedicine 2020The integration of NIR photothermal therapy and chemotherapy is considered as a promising technique for future cancer therapy. Hollow Prussian nanospheres have attracted...
BACKGROUND
The integration of NIR photothermal therapy and chemotherapy is considered as a promising technique for future cancer therapy. Hollow Prussian nanospheres have attracted much attention due to excellent near-infrared photothermal conversion effect and drug-loading capability within an empty cavity. However, to date, the hollow Prussian nanospheres have been prepared by a complex procedure or in organic media, and their shell thickness and size cannot be controlled. Thus, a simple and controllable route is highly desirable to synthesize hollow Prussian nanospheres with controllable parameters.
MATERIALS AND METHODS
Here, in our designed synthesis route, the traditional FeCl precursor was replaced with FeO nanospheres, and then the Prussian blue (PB) nanoparticles were engineered into hollow-structured PB (HPB) nanospheres through an interface reaction, where the FeO colloidal template provides Fe ions. The reaction mechanism and control factors of HPB nanospheres were systematically investigated. Both in vitro and in vivo biological effects of the as-synthesized HPB nanospheres were evaluated in detail.
RESULTS
Through systematical experiments, a solvent-mediated interface reaction mechanism was put forward, and the parameters of HPB nanospheres could be easily adjusted by growth time and template size under optimal water and ethanol ratio. The in vitro tests show the rapid and remarkable photothermal effects of the as-prepared HPB nanospheres under NIR laser irradiation (808 nm). Meanwhile, HPB nanospheres also demonstrated a high DOX loading capacity of 440 mg g as a drug carrier, and the release of the drug can be regulated by the heat from PB shell under the exposure of an NIR laser. The in vivo experiments confirmed the outstanding performance of HPB nanospheres in photothermal/chemo-synergistic therapy of cancer.
CONCLUSION
A solvent-mediated template route was developed to synthesize hollow Prussian blue (HPB) nanospheres in a simple and controllable way. The in vitro and in vivo results demonstrate the as-synthesized HPB nanospheres as a promising candidate due to their low toxicity and high efficiency for cancer therapy.
Topics: Combined Modality Therapy; Doxorubicin; Drug Carriers; Ferric Compounds; Ferrocyanides; Humans; Hyperthermia, Induced; Nanospheres; Phototherapy
PubMed: 32764943
DOI: 10.2147/IJN.S252505 -
BMC Health Services Research Jan 2023Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first...
BACKGROUND
Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service.
METHODS
For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results.
RESULTS
In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT).
CONCLUSIONS
If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML.
TRIAL REGISTRATION
Not applicable.
Topics: Humans; Gemtuzumab; Cost-Effectiveness Analysis; State Medicine; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Italy; Treatment Outcome; Sialic Acid Binding Ig-like Lectin 3
PubMed: 36642712
DOI: 10.1186/s12913-023-09054-x -
British Journal of Haematology Jan 2020Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic... (Review)
Review
Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic chemotherapy, has a higher relapse rate, and a worse prognosis. Secondary AML (sAML) is a heterogeneous disease, both biologically and clinically, even within the World Health Organization subgroups of sAML. Outcomes are the poorest in subgroups with sAML arising from an antecedent haematologic disorder which has been previously treated (ts-AML), and sAML in patients <55 years of age. This review describes the suboptimal outcomes of contemporary therapy, to support the notion of an unmet need for innovative treatment strategies in sAML. Despite the recent approval of CPX-351, long-term outcomes for this high-risk disease remain dismal. Resistance mechanisms to intensive chemotherapy contribute to relapse. Targeted immune therapy may avoid multidrug resistance mechanisms, but are unlikely to provide long-term remission due to a complex and rapidly evolving clonal disease profile. Advances for sAML will likely be accomplished by CAR T cell therapy or bispecific antibodies providing a bridge to allogeneic stem cell transplantation. Therefore, focus should be placed on novel strategies that can augment the untargeted effector function of allogeneic grafts.
Topics: Age Factors; Allografts; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Remission Induction; Stem Cell Transplantation
PubMed: 31863469
DOI: 10.1111/bjh.16354