Valproic acid may increase chemotherapy response

Valproic acid affects healthy hematopoietic stem cells (HSC) in a manner that is distinctly different from that exerted on leukemic cells. Reporting in the April 1st issue of Cancer Research, German researchers suggest that by stimulating proliferation of HSC, valproic acid could increase cancer patients’ response to conventional chemotherapy.

Valproic acid is a histone deacetylase inhibitor previously suggested for treatment of acute myeloid leukemia (AML) and other cancers (see Reuters Health reports, January 6, 2005 and December 27, 2001). Studies had shown that the agent selectively induces differentiation and apoptosis of leukemia cells. The research team, led by Dr. Martin Ruthardt, has found that “patients responding to this therapy frequently developed constant or increased bone marrow cellularity despite a remarkable blast cell reduction and peripheral hypergranulocytosis.”For their current report, Dr. Ruthardt and colleagues at Klinikum der Johann Wolfgang Goethe-Universitat in Frankfurt investigated the effects of valproic acid on normal cultured hematopoietic stem cells.In contrast to AML cells, valproic acid increased the proliferation of human CD34+ HSCs, but prevented them from differentiating into CD14+ cells. The agent also enhanced the replating efficiency of the cultured cells, suggesting that their self-renewal potential was enhanced. This was confirmed when valproate-treated stem cells were injected into lethally irradiated mice, and their spleen size was increased compared with control animals or those inoculated with all-trans retinoic acid.Valproic acid was also found to accelerate cell cycle progression by increasing the percentage of cells in S phase and reducing those in G1 phase.This process was apparently effected by inhibiting glycogen synthase kinase (GSK)-3-beta, the authors report.”The valproic acid-induced entry of quiescent hematopoietic and leukemic stem cells into the cell cycle could render them more susceptible to conventional chemotherapy, resulting either in a prolonged aplasia due to a higher efficiency of the therapy or in a shortened aplasia owing to the enforced proliferation of the normal hematopoiesis,” Dr. Ruthardt’s team concludes.(Source: Cancer Res 2005;65:2537-2541: Reuters Health: Oncolink: April 2005.)