التفاصيل البيبلوغرافية
| العنوان: |
A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia. |
| المؤلفون: |
Carbó, José M.1,2 (AUTHOR), Cornet-Masana, Josep M.1 (AUTHOR), Cuesta-Casanovas, Laia1,3 (AUTHOR), Delgado-Martínez, Jennifer1,4 (AUTHOR), Banús-Mulet, Antònia1 (AUTHOR), Clément-Demange, Lise2 (AUTHOR), Serra, Carme5,6 (AUTHOR), Catena, Juanlo5,6 (AUTHOR), Llebaria, Amadeu5 (AUTHOR), Esteve, Jordi1,7,8 (AUTHOR), Risueño, Ruth M.1 (AUTHOR) risueno@carrerasresearch.org |
| المصدر: |
Cancers. Mar2023, Vol. 15 Issue 6, p1912. 19p. |
| مصطلحات موضوعية: |
*THERAPEUTIC use of antineoplastic agents, *LYSOSOMES, *DRUG discovery, *ANIMAL experimentation, *AUTOPHAGY, *TETRACYCLINES, *APOPTOSIS, *CANCER patients, *CELLULAR signal transduction, *RESEARCH funding, *MOLECULAR structure, *MICE |
| مستخلص: |
Simple Summary: In spite of the recent expansion of the therapeutic landscape for acute myeloid leukemia (AML), resistance mechanisms and relapsed disease still pose a serious barrier to achieve curation for most patients. Considering the high inter- and intrapatient heterogeneity, disruptive therapeutic approaches are expected to provide a clinical solution for this unmet need. An in silico drug discovery program identified a new family of lysosome- and mitochondria-targeting compounds that specifically eradicate leukemia ex vivo and in vivo in relevant preclinical models by inducing both mitochondrial damage and apoptosis, and the simultaneous lysosomal membrane leakiness. Moreover, the compounds are effective in a wide panel of cancer cell lines, as their mechanism of action targets a common neoplastic feature. These compounds possess adequate pharmacological properties rendering them promising drug candidates for AML and unrelated neoplasias, and support their further clinical development. Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias. [ABSTRACT FROM AUTHOR] |
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