title: Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia.
abstract: Evading apoptosis is a hallmark of B-cell chronic lymphocytic leukemia (CLL) cells and an obstacle to current chemotherapeutic approaches. Inhibiting histone deacetylase (HDAC) has emerged as a promising strategy to induce cell death in malignant cells. We have previously reported that the HDAC inhibitor MGCD0103 induces CLL cell death by activating the intrinsic pathway of apoptosis. Here, we show that MGCD0103 decreases the autophagic flux in primary CLL cells. Activation of the PI3K/AKT/mTOR pathway, together with the activation of caspases, and to a minor extent CAPN1, resulting in cleavage of autophagy components, were involved in MGCD0103-mediated inhibition of autophagy. In addition, MGCD0103 directly modulated the expression of critical autophagy genes at the transcriptional level that may contribute to autophagy impairment. Besides, we demonstrate that autophagy is a pro-survival mechanism in CLL whose disruption potentiates cell death induced by anticancer molecules including HDAC and cyclin-dependent kinase inhibitors. In particular, our data highlight the therapeutic potential of MGCD0103 as not only an inducer of apoptosis but also an autophagy suppressor in both combination regimens with molecules like flavopiridol, known to induce protective autophagy in CLL cells, or as an alternative to circumvent undesired immunomodulatory effects seen in the clinic with conventional autophagy inhibitors.
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: V
authors.initials: V
authors.lastname: El-Khoury
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: S
authors.initials: S
authors.lastname: Pierson
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: E
authors.initials: E
authors.lastname: Szwarcbart
authors.affiliation: Flow Cytometry Core Facility, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: N H C
authors.initials: NH
authors.lastname: Brons
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: O
authors.initials: O
authors.lastname: Roland
authors.affiliation: Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: S
authors.initials: S
authors.lastname: Cherrier-De Wilde
authors.affiliation: Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: L
authors.initials: L
authors.lastname: Plawny
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors.forename: E
authors.initials: E
authors.lastname: Van Dyck
authors.affiliation: 1] Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg [2] Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: G
authors.initials: G
authors.lastname: Berchem
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002154:Calpain / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D001549:Benzamides; D002154:Calpain; D005419:Flavonoids; D056572:Histone Deacetylase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C077990:alvocidib; C523184:mocetinostat; C546842:MTOR protein, human; C484806:CAPN1 protein, human