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The backbone of induction therapy in acute myeloid leukaemia (AML) is to use an anthracycline in combination with cytarabine. Despite recent advances in AML therapy, this treatment remains the standard, and it has been largely unchanged for decades. There are few curative options for patients unfit for this treatment. The anti-protozoal agent emetine improves efficacy of anthracycline treatment towards AML in vitro and in vivo but the effect is more potent when emetine is administered 30 minutes after anthracyclines. To delay the onset of protein synthesis inhibition we produced a novel inactive emetine prodrug and co-encapsulated this with the anthracycline daunorubicin (DNR) in liposomes. Nanoencapsulation protects the prodrug from degradation in the blood and ensure simultaneous delivery of both drugs to cancer cells. The prodrug concept will delay the onset of action of emetine relative to DNR. In AML cells, the combination of DNR and the emetine-prodrug in liposomes increased cytotoxicity compared to liposomes with DNR and native emetine. Liposomes loaded with the emetine prodrug did not show increased toxicity towards non-cancerous cell lines and zebrafish larvae. In patients, a liposomal formulation such as that presented herein could allow for a reduced DNR dose without compromising efficacy, thereby reducing toxic side effects and enabling improved therapy for patients not fit for current treatment options., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Lars Herfindal reports financial support was provided by Childhood Cancer Association. Edvin Tang Gundersen reports financial support was provided by Western Norway Regional Health Authority. Ingeborg N Reiten reports financial support was provided by Research Council of Norway. Francois-Xavier Legrand reports financial support was provided by National Centre for Scientific Research. David Chapron reports financial support was provided by National Centre for Scientific Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC 50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3β and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

We synthesized new analogues of the anti-AML agent VS-II-173. We studied the effect of the substitution at the 1- and 5-positions of the pyrazolo[4,3-a]phenanthridine scaffold on Pim-1 kinase inhibition and cytotoxicity against AML MOLM-13 cells. We found that compounds 20 and 21, substituted at the 1-position exhibited stronger Pim-1 inhibition together with a high potency toward MOLM-13 cells, associated with apoptosis induction and selectivity over non-cancerous NRK cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3- a ]carbazole-3-carbaldehyde, pyrazolo[3,4- c ]carbazole, pyrazolo[4,3- a ]phenanthridine, or pyrrolo[2,3- g ]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC 50 below 5 μmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase-mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML., (©2019 American Association for Cancer Research.)

Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite technological advances in the field of medicine and our heightened knowledge regarding the pathogenesis of AML, the initial therapy of "7+3" Cytarabine and Daunorubicin has remained mainly unchanged since 1973. AML is a disease of the elderly, and increased morbidity in this patient group does not allow the full use of the treatment and drug-resistant relapse is common. Nanocarriers are drug-delivery systems that can be used to transport drugs to the bone marrow and target Leukemic Stem Cells (LSC), conferring less side-effects compared to the free-drug alternative. Nanocarriers also can be used to favour the transport of drugs that otherwise would not have been used clinically due to toxicity and poor efficacy. Liposomes are a type of nanocarrier that can be used as a dedicated drug delivery system, which can also have active ligands on the surface in order to interact with antigens on the target cells or tissues. In addition to using small molecules, it is possible to attach antibodies to the liposome surface, generating so-called immunoliposomes. By using immunoliposomes as a drug-delivery system, it is possible to minimize the toxic side effects caused by the chemotherapeutic drug on healthy organs, and at the same time direct the drugs towards the remaining AML blasts and stem cells. This article aims to explore the possibilities of using immunoliposomes as a drug carrier in AML therapy. Emphasis will be on possible target molecules on the AML cells, leukaemic stem cells, as well as bone marrow constituents relevant to AML therapy. Further, some conditions and precautions that must be met for immunoliposomes to be used in AML therapy will be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

Chemotherapy for AML is hampered by severe side-effects and failure to eliminate all the blasts that eventually leads to relapse. The use of nanosized particulate drug carriers such as liposomes and polymeric nanoparticles has the potential to improve AML therapy by delivering more of the drug to the disease site, thereby reducing toxicity. For example, encapsulation in liposomes reduces the cardiotoxicity of anthracyclines, giving an improved therapeutic index. Moreover, when the surface properties are engineered appropriately, nanocarriers remain in the circulation and extravasate in tissues with sinusoidal capillaries, one of which is bone marrow, leading to a more favourable distribution of the associated drug. Drug carrier technology contributes to the development of newer drugs, such as nucleic acids that can be protected from degradation and delivered into cells, thus opening the way for gene-silencing strategies. Furthermore, carrier systems provide a means of dispersing poorly water-soluble molecule for in vivo administration and thus increase the "druggability" of new lead compounds, such as heat-shock protein inhibitors. Particulate carriers can transport more than one active agent, allowing synergistic action and theranostic strategies. Notably, phase I and II clinical trials are being performed with CPX-351, a liposomal formulation containing cytarabine and daunorubicin at an optimal ratio. Finally, by attaching suitable ligands to the nanocarrier surface, specific targeting to AML cells can be achieved. In this review, we give examples of successful targeting to folate and transferrin receptors against AML.

The synthesis of new pyrrolocarbazoles substituted at N-1/N-10 positions is described. All the compounds tested demonstrated moderate to high Pim-1/Pim-3 kinase inhibitory potency. The most active inhibitors identified in this series (3, 17) have an alkyl chain bridging the N-1 and N-10 positions. These compounds (3, 17) exhibited apoptosis-inducing activity toward acute myeloid leukemia IPC-81 cells, but not toward normal fibroblasts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Despite recent advances in chemotherapy against acute myeloid leukaemia (AML), the disease still has high mortality, particularly for patients who tolerate extensive chemotherapy poorly. Nano-formulations have potential to minimise the adverse effects of chemotherapy. We present here a liposomal formulation encapsulating both the anthracycline daunorubicin (DNR) and emetine (Eme) for enhanced cytotoxic effect against AML cells. Eme could be loaded into the PEGylated liposomes together with DNR by the acid precipitation principle, with a loading efficiency of Eme at about 50% of that of DNR. The liposome surface was modified with folate to enhance drug loading into cells, giving higher cytotoxic activity. Both intracellular drug loading and cytotoxic activity could be further increased by anti-folate treatment of AML cells with methotrexate (MTX). The combination of DNR and Eme also increased drug loading in MTX-treated cells compared to DNR alone. Liposomes with both DNR and Eme were particularly efficient against AMLs with deficient p53. In conclusion, we have produced a multi-functional liposomal anti-leukaemic drug formulation designed to overcome some of the problems in anthracycline chemotherapy: (1) Combination of DNR and Eme to diminish drug resistance. (2) Using PEGylated stealth liposomes to minimise adverse side-effects. (3) Molecules on the liposomal surface target proteins on AML-cells ensure selectivity, which was enhanced by priming the leukaemia cells with MTX., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81) cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T) fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML) activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells.

The potential of marine benthic cyanobacteria as a source of anticancer drug candidates was assessed in a screen for induction of cell death (apoptosis) in acute myeloid leukemia (AML) cells. Of the 41 marine cyanobacterial strains screened, more than half contained cell death-inducing activity. Several strains contained activity against AML cells, but not against non-malignant cells like hepatocytes and cardiomyoblasts. The apoptotic cell death induced by the various strains could be distinguished by the role of caspase activation and sensitivity to the recently detected chemotherapy-resistance-associated prosurvival protein LEDGF/p75. One strain (M44) was particularly promising since its activity counteracted the protective effect of LEDGF/p75 overexpressed in AML cells, acted synergistically with the anthracycline anticancer drug daunorubicin in AML cells, and protected cardiomyoblasts against the toxic effect of anthracyclines. We conclude that culturable benthic marine cyanobacteria from temperate environments provide a promising and hitherto underexploited source for novel antileukemic drugs.

Intensive chemotherapy for acute myelogenous leukaemia (AML) results in an overall long-term disease-free survival of < 50%. This percentage reflects an improved survival for certain subsets of patients with low-risk cytogenetic abnormalities after treatment with high-dose cytarabine, whereas lower long-term survival is seen for other patients and especially for the large group of elderly patients. New treatment strategies are therefore considered in AML and one approach is to target the regulation of apoptosis in AML cells with new pharmacological agents. Regulation of apoptosis seems to be clinically important in AML as intracellular levels of apoptosis-regulating mediators can be used as predictors of prognosis in AML. It is also well documented that cytotoxic drugs exert important antileukaemic effects through induction of apoptosis. Marine toxins represent new pharmacological agents with proapoptotic effects and should be considered for combination therapy with cytotoxic drugs. These agents are already useful laboratory tools for in vitro studies of AML cells but it is still too early to conclude whether they will become useful in clinical therapy. One of the major problems to be investigated is the toxicity of combination therapy, although this may be solved by the coupling of toxins to antibodies or growth factors with a preferential binding to AML cells. Other problems that have to be addressed are the possible effect of the toxins' tumour promoting effects on chemosensitivity in relapsed AML and the possibility of cross-resistance between cytotoxic drugs and toxins.