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Inhibition of leukemic cell growth by a novel anti‐cancer drug (GUT‐70) from calophyllum brasiliense that acts by induction of apoptosis
Author(s) -
Kimura Shinya,
Ito Chihiro,
Jyoko Naoto,
Segawa Hidekazu,
Kuroda Junya,
Okada Masayuki,
Adachi Souichi,
Nakahata Tatsutoshi,
Yuasa Takeshi,
Filho Valdir Cechinel,
Furukawa Hiroshi,
Maekawa Taira
Publication year - 2004
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.20505
Subject(s) - apoptosis , leukemia , biology , cancer cell , cell culture , growth inhibition , cell growth , haematopoiesis , cancer , pharmacology , chemistry , biochemistry , stem cell , microbiology and biotechnology , immunology , genetics
During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT‐70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT‐70, characterized as a tricyclic coumarin, 5‐methoxy‐2,2‐dimethyl‐6‐(2‐methyl‐1‐oxo‐2‐butenyl) ‐10‐propyl‐2 H ,8 H ‐benzo[1,2‐ b ;3,4‐ b′ ]dipyran‐8‐one (C 23 H 26 O 5 ), inhibited all 6 human leukemic cell lines evaluated, including the P‐glycoprotein overexpressing cell line, in a concentration and time‐dependent manner with IC 50 values from 2–5 μM. Furthermore, GUT‐70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 μM and also did not inhibit the proliferation of normal human hepatocytes up to 30 μM. GUT‐70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT‐70 induced anti‐leukemic effects independent of the p53‐p2l WAFl/CIP1 pathway and increased the overall expression of p27 KIP1 and p57 KIP2 , to stop the cell cycle at the G 1 /S transition. Thus, a novel anti‐cancer drug, GUT‐70 isolated from the stem bark of C. brasiliense induces caspase‐mediated and p53‐independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics.