In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma

Ocio, Enrique M.; Vilanova, David; Atadja, Peter; Maiso, Patricia; Crusoé, Edvan; Fernández-Lázaro, Diego; Garayoa, Mercedes; San-Segundo, Laura; Hernández-Iglesias, Teresa; Álava, Enrique de; Shao, Wenlin; Yao, Yung-Mae; Pandiella, Atanasio; San-Miguel, Jesús F.

doi:10.3324/haematol.2009.015495

Cited by 143 publications

(103 citation statements)

References 34 publications

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“…2 ), 31 where a corresponds to the longest diameter and b to the shortest diameter measured. For each individual rat, the total vesicle volume was calculated by adding up the individual volumes of the developed vesicles.…”

Section: Animal Modelmentioning

confidence: 99%

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

et al. 2016

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Studies have examined how endometriosis interacts with the nervous system, but little attention has been paid to opioidergic systems, which are relevant to pain signaling. We used the autotransplantation rat model of endometriosis and allowed to progress for 60 days. The brain was collected and examined for changes in endogenous opioid peptides, mu opioid receptors (MORs), and the N-methyl-D-aspartate subunit receptor (NR1) in the periaqueductal gray (PAG), since both of these receptors can regulate PAG activity. No changes in endogenous opioid peptides in met-and leu-enkephalin or b-endorphin levels were observed within the PAG. However, MOR immunoreactivity was significantly decreased in the ventral PAG in the endometriosis group. Endometriosis reduced by 20% the number of neuronal profiles expressing MOR and reduced by 40% the NR1 profiles. Our results suggest that endometriosis is associated with subtle variations in opioidergic and glutamatergic activity within the PAG, which may have implications for pain processing.

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Section: Animal Modelmentioning

confidence: 99%

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

et al. 2016

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“…To reduce the potential for nonspecific effects, the inhibitors were used at the lowest IC 50 doses reported to result in effective histone deacetylase (HDAC)-1 and pan-HDAC inhibition, [31,32] or Dimethyl Sulfoxide (DMSO; vehicle control). Cell viability was quantified by evaluation of ATP levels using CellTiter-Glo (Promega, Madison, WI, http:// www.promega.com).…”

Section: Ex Vivo Entinostat Treatmentmentioning

confidence: 99%

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

et al. 2013

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The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis, and therapeutic intervention based on improved patient stratification. Relevant preclinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML), and a conditional transplantation mouse model was developed that demonstrated oncogene dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity map analysis identified Entinostat as a drug with the potential to alter the leukemic condition toward the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation, and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal

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“…A study reported, addition of panobinostrat, to either bortezomib/dexamethasone (PBD) or lenalidomide /dexamethasone (PLD) resulted in a synergistic effect in all: MM cell lines, fresh myeloma cells and plasmacytoma murine models. 166 Another study also showed that PBD may be effective in relapsed and velcade refractory patients. 167 The combination of panobinostat, Velcade, and dexamethasone is currently being tested in a Phase 3 clinical trial, Panobinostat is also being studied in combination with other common anti-myeloma drugs, including Revlimid, carfilzomib and pomalidomide.…”

Section: New Therapies / Future Perspectives/ New Investigational Agentsmentioning

confidence: 99%

Multiple myeloma: the disease and its treatment

Gupta¹,

Pal²,

Tikoo³

2013

Int J Basic Clin Pharmacol

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Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products and the host response to it result in a number of organ dysfunctions and symptoms of bone pain, fracture, anemia, hypercalcemia, susceptibility to infection, neurologic symptoms, clotting abnormalities and manifestations of hyperviscosity. The cause of myeloma remains unexplained but it is associated with few occupations, inflammatory conditions, autoimmune illnesses, viral infections and genetic heterogeneity. Direct interaction between multiple myeloma cells and bone marrow cells activates pleiotropic signalling pathways that mediate growth, survival, migration of multiple myeloma cells and also resistance to chemotherapy. Although myeloma remains incurable, but the use of novel drugs like thalidomide, lenalidomide and bortezomib have resulted in a paradigm change in the therapy of myeloma. Their inclusion in current multiple myeloma treatment regimens have extended median overall survival especially in younger patient population. Recent advances in the molecular genetics have provided opportunities to design highly specific inhibitors of signal transduction pathways that may enhance the efficacy of standard chemotherapy drugs by reducing or altering the pathways associated with cell survival. Despite therapeutic advances, multiple myeloma ultimately relapses and remains an incurable disease. Current research goals are to further increase our knowledge, to identify additional targeted therapies, and to reduce adverse effects and improve response rate. This review focuses on recent clinical advancement in ant myeloma strategies with additional discussion dedicated to emerging drugs that may prove beneficial to patients with this disease. [Int J Basic Clin Pharmacol 2013; 2(2.000): 103-121

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In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma

Abstract: The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.

Cited by 143 publications

References 34 publications

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

Multiple myeloma: the disease and its treatment

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