A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia
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...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/6/1912 |
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| author | José M. Carbó Josep M. Cornet-Masana Laia Cuesta-Casanovas Jennifer Delgado-Martínez Antònia Banús-Mulet Lise Clément-Demange Carme Serra Juanlo Catena Amadeu Llebaria Jordi Esteve Ruth M. Risueño |
| author_facet | José M. Carbó Josep M. Cornet-Masana Laia Cuesta-Casanovas Jennifer Delgado-Martínez Antònia Banús-Mulet Lise Clément-Demange Carme Serra Juanlo Catena Amadeu Llebaria Jordi Esteve Ruth M. Risueño |
| author_sort | José M. Carbó |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup>–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. |
| first_indexed | 2024-03-11T06:48:50Z |
| format | Article |
| id | doaj.art-a3883d1edb324b498e711d33d23fc9f4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T06:48:50Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a3883d1edb324b498e711d33d23fc9f42023-11-17T10:08:57ZengMDPI AGCancers2072-66942023-03-01156191210.3390/cancers15061912A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating LeukemiaJosé M. Carbó0Josep M. Cornet-Masana1Laia Cuesta-Casanovas2Jennifer Delgado-Martínez3Antònia Banús-Mulet4Lise Clément-Demange5Carme Serra6Juanlo Catena7Amadeu Llebaria8Jordi Esteve9Ruth M. Risueño10Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainLeukos Biotech, 08021 Barcelona, SpainMCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, SpainMCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, SpainMCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, SpainAcute 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 Ca<sup>2+</sup>–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.https://www.mdpi.com/2072-6694/15/6/1912leukemiadrug discoveryautophagyapoptosisnew chemical entitylysosome |
| spellingShingle | José M. Carbó Josep M. Cornet-Masana Laia Cuesta-Casanovas Jennifer Delgado-Martínez Antònia Banús-Mulet Lise Clément-Demange Carme Serra Juanlo Catena Amadeu Llebaria Jordi Esteve Ruth M. Risueño A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia Cancers leukemia drug discovery autophagy apoptosis new chemical entity lysosome |
| title | A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia |
| title_full | A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia |
| title_fullStr | A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia |
| title_full_unstemmed | A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia |
| title_short | A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia |
| title_sort | novel family of lysosomotropic tetracyclic compounds for treating leukemia |
| topic | leukemia drug discovery autophagy apoptosis new chemical entity lysosome |
| url | https://www.mdpi.com/2072-6694/15/6/1912 |
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