Current Understandings of Myeloid Differentiation Inducers in Leukemia Therapy

Takahashi, Shinichiro

doi:10.1159/000510980

Cited by 13 publications

(9 citation statements)

References 82 publications

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“…The concept of differentiation therapy emerged from the fact that hormones or cytokines may promote differentiation ex vivo, thereby irreversibly changing the phenotype of cancer cells 29 . In hematologic malignancies, especially in acute promyelocytic leukemia, differentiation therapy is widely used 29,30 , but in solid tumors, the effect of differentiation therapy is still unsatisfactory 31 . The deficiency of MAL in OSCCs represents poor differentiation of cancer cells, which suggested we might reverse the process of tumor dedifferentiation by rebooting regulatory network of MAL .…”

Section: Discussionmentioning

confidence: 99%

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

Chen

Zhu

Liu

et al. 2021

Preprint

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Oral squamous cell carcinoma (OSCC) is widely recognized as an optimal model for precise medicine guided molecular biomarkers of cancer, however, few clinical practices were applied till now. Based on the data from our own studies and published papers, it was found that the expression of MAL was significantly decreased in epithelial cancer as compared with normal tissues, and exhibited a opposite association with pathological grade. To study the molecular events related to deficiency of MAL during carcinogenesis, occurrence and development, a Mal knockout mouse model was constructed and consistently reproduced and bred. The Mal knockout mice are highly vulnerable to tumor induction by carcinogen of 4NQO, evidenced by their extremely earlier carcinogenesis, higher incidence, and more aggressive growth. Analysis of scRNA-seq data indicated that Mal knockout mice lost the ability in maintaining epithelial cell differentiation and get more prone to carcinogen with a remarkably higher incidence of epithelial malignancy. Further analyses identified putative co-functional genes of MAL, including DSG1, AQP3 and S100A8, which are key factors in maintaining epithelial cell differentiation. To conclude, the current study exhibits the clinical significance and explains the tumor suppressing function of MAL. The results also suggest the potential of MAL and its co-functional genes being biomarkers for designing the prevention and/or differentiation therapy strategies in OSCC.SignificanceMAL is found to be strongly opposite with tumor pathological grade from clinical and in vivo studies in OSCC. We propose MAL and its co-functional genes, including DSG1, AQP3 and S100A8, as key factors in maintaining epithelial cell differentiation and are valuable targets for designing prevention and differentiation therapy strategies in OSCC.

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Section: Discussionmentioning

confidence: 99%

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

Chen

Zhu

Liu

et al. 2021

Preprint

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“…Acute myelocytic leukemias (AMLs) are eminently suitable to demonstrate therapy-related induction of differentiation both, morphologically and functionally (7,67). Currently there is choice of a series of approved drugs, cytosine arabinoside (AraC), FLT3 inhibitors and inhibitors of the mutant IDH1/ IDH2, all characterized to induce to some degree differentiation in AML.…”

Section: Differentiationmentioning

confidence: 99%

“…Currently there is choice of a series of approved drugs, cytosine arabinoside (AraC), FLT3 inhibitors and inhibitors of the mutant IDH1/ IDH2, all characterized to induce to some degree differentiation in AML. Another series of drugs, namely inhibitors of BET protein, DOTIL1 and HDAC, showed differentiation induction in vitro, and in animal models, but failed to show decisive clinical activity so far (67). To what extent tyrosine kinase inhibitors with differential activity profiles are active in AML patients without mutated FLT3 remains an open question addressed in ongoing trials.…”

Section: Differentiationmentioning

confidence: 99%

Drug Repurposing by Tumor Tissue Editing

et al. 2022

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The combinatory use of drugs for systemic cancer therapy commonly aims at the direct elimination of tumor cells through induction of apoptosis. An alternative approach becomes the focus of attention if biological changes in tumor tissues following combinatory administration of regulatorily active drugs are considered as a therapeutic aim, e.g., differentiation, transdifferentiation induction, reconstitution of immunosurveillance, the use of alternative cell death mechanisms. Editing of the tumor tissue establishes new biological ‘hallmarks’ as a ‘pressure point’ to attenuate tumor growth. This may be achieved with repurposed, regulatorily active drug combinations, often simultaneously targeting different cell compartments of the tumor tissue. Moreover, tissue editing is paralleled by decisive functional changes in tumor tissues providing novel patterns of target sites for approved drugs. Thus, agents with poor activity in non-edited tissue may reveal new clinically meaningful outcomes. For tissue editing and targeting edited tissue novel requirements concerning drug selection and administration can be summarized according to available clinical and pre-clinical data. Monoactivity is no pre-requisite, but combinatory bio-regulatory activity. The regulatorily active dose may be far below the maximum tolerable dose, and besides inhibitory active drugs stimulatory drug activities may be integrated. Metronomic scheduling often seems to be of advantage. Novel preclinical approaches like functional assays testing drug combinations in tumor tissue are needed to select potential drugs for repurposing. The two-step drug repurposing procedure, namely establishing novel functional systems states in tumor tissues and consecutively providing novel target sites for approved drugs, facilitates the systematic identification of drug activities outside the scope of any original clinical drug approvals.

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“…One agent that is used in treatment of AML, is the nucleoside cytosine arabinoside [129]. In fact, cytosine arabinoside (cytarabine, ara-C), in high concentrations (>50 uM) inhibits NFκB in some cell types to a certain extent; yet this inhibition is evidently not enough, since after development of drug resistance, ara-C does not suffice as monotherapy for AML [130][131][132].…”

Section: Pathways Signaling To Nfκb Function In Aml Stem Cellsmentioning

confidence: 99%

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

Dancik¹,

Voutsas²,

Vlahopoulos³

2022

Front. Biosci. (Schol Ed)

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The enzymes that belong to the aldehyde dehydrogenase family are expressed in a variety of cells; yet activity of their main members characterizes stem cells, both normal and malignant. Several members of this family perform critical functions in stem cells, in general, and a few have been shown to have key roles in malignant tumors and their recurrence. In particular, ALDH1A1, which localizes to the cytosol and the nucleus, is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemiainitiating cells from a number of antineoplastic agents, and proves vital for the establishment of human AML xenografts in mice. ALDH2, which is located in mitochondria, has a major role in alcohol metabolism by clearing ethanol-derived acetaldehyde. Haematopoietic stem cells require ALDH2 for protection against acetaldehyde, which can cause damage to DNA, leading to insertions, deletions, chromosomal rearrangements, and translocations. Mutations compromise stem cell function, and thereby threaten blood homeostasis. We review here the potential of targeting the enzymatic activity of aldehyde dehydrogenases in acute leukemia.

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Current Understandings of Myeloid Differentiation Inducers in Leukemia Therapy

Cited by 13 publications

References 82 publications

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

Drug Repurposing by Tumor Tissue Editing

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

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