Hydrogen peroxide overproduced in breast cancer cells can serve as an anticancer prodrug generating apoptosis-stimulating hydroxyl radicals under the effect of tamoxifen-ferrocene conjugate.
A new approach to the treatment of cancer is suggested, based on the innate overproduction of hydrogen peroxide in cancer cells. Hydrogen peroxide serves as a prodrug in the presence of transition metal ions, such as iron delivered by ferrocene. Under the effect of ferrocene, hydrogen peroxide is split into hydroxyl anions and highly reactive hydroxyl radicals. The latter cause oxidative DNA damage, which induces apoptosis, leading to elimination of cancer cells. Tamoxifen, a drug that interacts with oestrogen receptors, was used as a carrier to deliver ferrocene to breast cancer cells. For this aim tamoxifen conjugated to ferrocene (Tam-Fer) was synthesized. We have shown that the frequency of apoptotic events in MCF-7 breast cancer cells treated with Tam-Fer is significantly higher than in cells treated with tamoxifen or ferrocene separately. The increase of apoptosis correlates well with the rise in generation of reactive oxygen species in cancer cells. These results show that the hydrogen peroxide overproduced in tumour cells can serve as a prodrug for the treatment of cancer.
Wlassoff
Wjatschesslaw A
WA
University of North Carolina, 2217-B, McGavran-Greenberg Hall, Chapel Hill, NC 27599-7400, USA.
Albright
Craig D
CD
Sivashinski
Michael S
MS
Ivanova
Anastasia
A
Appelbaum
Jacob G
JG
Salganik
Rudolph I
RI
D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism; D000075163:Metallocenes; D011355:Prodrugs; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D005296:Ferrous Compounds; D000075163:Metallocenes; D011355:Prodrugs; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013629:Tamoxifen; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; C004998:ferrocene