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The traditional Chinese herbal compound rocaglamide preferentially induces apoptosis in leukemia cells by modulation of mitogen‐activated protein kinase activities
Author(s) -
Zhu Jia Y.,
Lavrik In.,
Mahlknecht Ulrich,
Giaisi Marco,
Proksch Peter,
Krammer Peter H.,
LiWeber Min
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22883
Subject(s) - myeloid leukemia , mapk/erk pathway , apoptosis , leukemia , cancer research , p38 mitogen activated protein kinases , cancer , pharmacology , kinase , cancer cell , caspase , protein kinase a , medicine , immunology , programmed cell death , biology , microbiology and biotechnology , biochemistry
With an increasing cancer rate worldwide, there is an urgent quest for the improvement of anticancer drugs. One of the main problems of present chemotherapy in treatment of tumor patients is the toxicity of drugs. Most of the existent anticancer drugs, unfortunately, attack also proliferating normal cells. In recent years, traditional Chinese herbal remedies have gradually gained considerable attention as a new source of anticancer drugs. Although their healing mechanisms are still largely unknown, some of the drugs have been used to help cancer patients fight their disease at reduced side effects compared to other treatments. In our study, we show that Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia , induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Investigation of the molecular mechanisms by which Roc kills tumors revealed that it induces a consistent activation of the stress‐response mitogen‐activated protein kinase (MAPK) p38 accompanied with a long‐term suppression of the survival MAPK extracellular signal‐regulated kinase. These events affect proapoptotic Bcl‐2 family proteins leading to depolarization of the mitochondrial membrane potential and trigger caspase‐mediated apoptosis involving caspase‐9, ‐8, ‐3 and ‐2. Importantly, Roc shows no effects on MAPKs in normal lymphocytes and therefore has no or very low toxicity on healthy cells. Up to now, more than 50 different Roc derivatives have been isolated from Aglaia . Our study suggests that Roc derivatives may be promising candidates for the development of new drugs against hematologic malignancies. © 2007 Wiley‐Liss, Inc.