Abstract
The development of novel chemotherapeutic drugs is needed for the treatment of patients with acute lymphoblastic leukemia (ALL). In this study, the anti-leukemic effect and the potential molecular mechanisms of action of flavokawain B on ALL were investigated. Flavokawain B was found to significantly inhibit the cellular proliferation of B-ALL and T-ALL cell lines in a dose-dependent manner. It also induced cellular apoptosis by increasing the expression of p53, Bax and Puma, and activating the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP). Furthermore, the enhancement of p53-dependent apoptosis by flavokawain B could be rescued by pifithrin-α, a pharmacological inhibitor of p53 transcriptional activity. Moreover, the proliferation of leukemia blast cells from 16 patients with ALL was inhibited by flavokawain B, and tumor growth in xenograft mice was also suppressed by this drug. In conclusion, our results demonstrate the therapeutic potential of flavokawain B for the treatment of ALL.
Keywords:
Flavokawain B; acute lymphoblastic leukemia (ALL); apoptosis; p53; proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Caspase 3 / metabolism
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Caspases / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Child
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Child, Preschool
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Female
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Flavonoids / pharmacology*
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Gene Expression
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Humans
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Infant
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Male
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Mice
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Poly(ADP-ribose) Polymerases / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / diagnosis
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Flavonoids
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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flavokawain B
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Poly(ADP-ribose) Polymerases
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Caspase 3
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Caspases