Anti-leukemic activity of valproic acid and imatinib mesylate on human Ph+ ALL and CML cells in vitro.
The armamentarium of anti-leukemic drugs has increased substantially since anti-leukemic activities were recently found for a variety of non-classical cytostatic drugs, among them the histone deacetylase (HDAC) inhibitor valproic acid (VPA). This study investigated the effect of VPA on proliferation and apoptosis of human Philadelphia chromosome-positive (Ph+) acute lymphatic (ALL) and chronic myeloid leukemia (CML) cells and on colony formation of human chronic-phase CML progenitor cells. Strong anti-proliferative and pro-apoptotic effects of VPA were observed on human ALL and CML cell lines at concentrations achievable in vivo. These effects were most pronounced in ALL cell lines as well as in primary ALL cells. Notably, VPA revealed enhanced activity with imatinib mesylate, nilotinib, the farnesyl transferase inhibitor SCH66336, interferon-alpha and cytosine arabinoside. VPA inhibited the growth of colony-forming cells from 12 Ph+ chronic-phase CML patients but also of those from normal healthy controls in a dose-dependent fashion. HDAC-inhibiting activity of VPA was confirmed on ALL and CML cells. In conclusion, VPA, whether alone or in combination with other non-classical anti-leukemic compounds, exerts significant anti-leukemic effects on human ALL and CML cells.
Kircher
Brigitte
B
Department of Internal Medicine V - Hematology and Oncology, Immunobiology and Stem Cell Laboratory, Innsbruck Medical University, Innsbruck, Austria. brigitte.kircher@i-med.ac.at
Schumacher
Petra
P
Petzer
Andreas
A
Hoflehner
Elisabeth
E
Haun
Margot
M
Wolf
Anna Maria
AM
Nachbaur
David
D
Gastl
Günther
G
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001549:Benzamides; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016313:Genes, abl; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D014635:Valproic Acid; D000068877:Imatinib Mesylate