Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from calophyllum brasiliense that acts by induction of apoptosis.

Abstract

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-2H,8H-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 microM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 microM and also did not inhibit the proliferation of normal human hepatocytes up to 30 microM. 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.

• Authors: Shinya Kimura, Chihiro Ito, Naoto Jyoko, Hidekazu Segawa, Junya Kuroda, Masayuki Okada, Souichi Adachi, Tatsutoshi Nakahata, Takeshi Yuasa, Valdir Cechinel Filho, Hiroshi Furukawa, Taira Maekawa
• Journal: International journal of cancer (Int J Cancer) Vol. 113 Issue 1 Pg. 158-65 (Jan 01 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15386357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Coumarins
• GUT-70
• Caspases

Topics

• Adenocarcinoma (drug therapy)
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Brazil
• Calophyllum
• Caspases (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• Coumarins (pharmacology)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Leukemia (drug therapy)