A novel iodomethylene-dimethyl-dihydropyranone induces G2/M arrest and apoptosis in human cancer cells.
BACKGROUND
The putative pharmacophore of a naturally cytotoxic limonoid haperforin B1, E-5-iodomethylene-6,6-dimethyl-5,6-dihydropyran-2-one (IDDP) was synthesized and its biological activity was investigated.


METHODS
The cytotoxicity of IDDP was assessed using human breast, lung, colorectal and epidermal carcinomas, chronic myeloid leukemia and glioblastoma cell lines. Cell cycle analysis was performed by flow cytometry. The induction of apoptosis was studied by a caspase assay and by annexin V-propidium iodide double staining. The organization of actin and tubulin microfilaments was analysed by immunocytochemical labeling.


RESULTS
IDDP was shown to inhibit the growth of a panel of human cancer cell lines independently of their p53 status with IC(50) ranging from 0.07 to 0.50 microM. All the treated cells were arrested in the G(2)/M phase in a time-dependent manner before cell death occurred through an apoptotic pathway. Immunocytochemical studies revealed that the normal organization of microfilaments and microtubules was disrupted in IDDP exposed cells.


CONCLUSIONS
IDDP can be considered as a promising anticancer agent.
Bignon
Jérôme
J
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91190 Gif-sur-Yvette, France. Jerome.Bignon@icsn.cnrs-gif.fr
Bénéchie
Michel
M
Herlem
Denyse
D
Liu
Jian-Miao
JM
Pinault
Alexia
A
Khuong-Huu
Françoise
F
Wdzieczak-Bakala
Joanna
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C543671:E-5-iodomethylene-6,6-dimethyl-5,6-dihydropyran-2-one; D011753:Pyrones