Depakote scientific update |
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Haematologica. 2007 Apr;92(4):542-5.
Bug G, Schwarz K, Schoch C, Kampfmann M, Henschler R, Hoelzer D, Ottmann OG, Ruthardt M.
Medizinische Klinik II, Abt. Hamatologie/Onkologie, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany.
Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia.
Histone deacetylase inhibitor valproic acid (VPA) was recently shown to enhance proliferation and self-renewal of normal hematopoietic stem cells, raising
the possibility that VPA may also support growth of leukemic progenitor cells (LPC). Here, VPA maintains a significantly higher proportion of CD34+ LPC and
colony forming units compared to control cultures in six AML samples, but selectively reduces leukemic cell numbers in another AML sample with expression of
AML1/ETO. Our data suggest a differential effect of VPA on the small population of AML progenitor cells and the bulk of aberrantly differentiated blasts in
the majority of AML samples tested.
Folia Biol (Praha). 2007;53(2):37-49.
Kostrouchova M, Kostrouch Z, Kostrouchova M.
Laboratory of Molecular Pathology, Institute of Inherited Metabolic Disorders of the 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
Valproic acid, a molecular lead to multiple regulatory pathways.
Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina
bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show
that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the
potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the
phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also
serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker
effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the
behaviour of cancer cells.
Int J Biochem Cell Biol. 2007 Mar 15;
Tsapis M, Lieb M, Manzo F, Shankaranarayanan P, Herbrecht R, Lutz P, Gronemeyer H.
Department of Cell Biology and Signal Transduction, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 10142, F-67404 Illkirch Cedex, C.U. de Strasbourg, France.
HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway.
Inhibitors of histone deacetylases (HDACi's) are promising novel tools for cancer therapy. We have compared the growth inhibitory and apoptogenic potential
of the pan-HDACi SAHA and the sub-class I selective HDAC inhibitor MS275, as well as valproic acid (VPA) on glucocorticoid sensitive and resistant B (B-ALL)
and T (T-ALL) cell acute lymphoblastic leukemia cells and patients blasts. In contrast, to our previous results with U937 acute myeloid leukemia (AML) cells
which showed a similar activity of MS275 and SAHA in growth inhibition and apoptosis induction, both B and T-ALL cells were much more efficiently killed by
SAHA and VPA than by MS275. The same relative potency was observed with some patient ALL blasts treated ex vivo. SAHA displayed similar efficacy on
glucocorticoid-sensitive and insensitive ALL cells but did not synergize with dexamethasone. In studying mediators of apoptosis we found that the TRAIL
receptor DR5 is constitutively expressed in glucocorticoid-sensitive CEM-C7 cells which are also TRAIL sensitive. In contrast, glucocorticoid-insensitive
CEM-C1 cells do not express DR5 and are insensitive to TRAIL. However, SAHA induces, in addition to p21(WAF1/CIP1) also re-expression of DR5. Importantly,
SAHA-induced apoptosis of CEM-C7 cells operates through initiator caspase 10, while it induces apotosis of CEM-C1 cells through the intrinsic, as well as
through caspase-independent death pathways. Our data suggest that the generation of resistance to glucocorticoids has dramatically altered death signaling in
these cells and that SAHA overcomes these restrictions by inducing alternative death pathways.
Drug Metab Dispos. 2007 May 11;
Wong H, Tong V, Riggs KW, Rurak DW, Abbott FS, Kumar S.
Genentech Inc.
Kinetics of Valproic Acid Glucuronidation: Evidence for In Vivo Autoactivation.
Sigmoidal or autoactivation kinetics have been observed in vitro for both cytochrome P450 and UDP-glucuronosyltransferase catalyzed enzymatic reactions.
However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. The current study investigates the kinetics of valproic
acid-glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). Following a 100 mg/kg i.v. bolus dose of
valproic acid (VPA) to adult sheep (n=5), the majority of the dose was recovered in urine as VPAG (~79%). Eadie-Hofstee plots of VPAG formation rate
(calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics, and provided estimates of Vmax(app), S50(app) and n of
2.10 +/- 0.75 micromol/min/kg, 117 +/- 56 microM and 1.34 +/- 0.14, respectively. Comparable estimates of Vmax(app) (2.63 +/- 0.33 micromol/min/kg), S50(app)
(118 +/- 53 microM) and n (2.06 +/- 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data
to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation
in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that
autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under the certain experimental conditions and
confirm its relevance.
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