Treatment of acute myeloid leukemia / Valproic acid

ironjustice@aol.com · medicine forum Guru Joined: 28 Apr 2005 Posts: 1522

Cancer Res. 2005 Apr 1;65(7):2537-41. Related Articles, Links

Valproic acid stimulates proliferation and self-renewal of
hematopoietic stem cells.

Bug G, Gul H, Schwarz K, Pfeifer H, Kampfmann M, Zheng X, Beissert T,
Boehrer S, Hoelzer D, Ottmann OG, Ruthardt M.

Medizinische Klinik II/Abteilung Hamatologie, Klinikum der Johann
Wolfgang Goethe-Universitat, Frankfurt, Germany.

Histone deacetylase inhibitors have attracted considerable attention
because of their ability to overcome the differentiation block in
leukemic blasts, an effect achieved either alone or in combination with
differentiating agents, such as all-trans retinoic acid. We have
previously reported favorable effects of the potent histone deacetylase
inhibitor valproic acid in combination with all-trans retinoic acid in
patients with advanced acute myeloid leukemia leading to blast cell
reduction and improvement of hemoglobin. These effects were accompanied
by hypergranulocytosis most likely due to an enhancement of nonleukemic
myelopoiesis and the suppression of malignant hematopoiesis rather than
enforced differentiation of the leukemic cells. These data prompted us
to investigate the effect of valproic acid on normal hematopoietic stem
cells (HSC). Here we show that valproic acid increases both
proliferation and self-renewal of HSC. It accelerates cell cycle
progression of HSC accompanied by a down-regulation of
p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by
phosphorylation on Ser9 accompanied by an activation of the Wnt
signaling pathway as well as by an up-regulation of HoxB4, a target
gene of Wnt signaling. Both are known to directly stimulate the
proliferation of HSC and to expand the HSC pool. In summary, we here
show that valproic acid, known to induce differentiation or apoptosis
in leukemic blasts, stimulates the proliferation of normal HSC, an
effect with a potential effect on its future role in the treatment of
acute myeloid leukemia.

PMID: 15805245 [PubMed - indexed for MEDLINE]

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