Medroxyprogesterone and tamoxifen augment anti-proliferative efficacy and reduce mitochondria-toxicity of epirubicin in FM3A tumor cells in vitro.
We have shown that low doses of medroxyprogesterone acetate (MPA- 2.6 microM) and tamoxifen (TAM- 270 nM) could augment the effectiveness of epirubicin in breast tumor cells. In this study, we monitored early cell kinetics (24-96 h plating and S-phase) and mitochondrial morphology during chemo-endocrine treatments to delineate the epirubicin sensitizing mechanism. S-phase fractions with radioactive thymidine uptake, plating efficacy, and transmission electron microscopic analysis were taken for 24-h periods until the 7th day after drug treatments. Despite strongly enhancing the clonogenic killing, both MPA and TAM did not affect epirubicin induced early cytotoxicity. Instead, they augmented the S-phase inhibition, which was even more pronounced for TAM. Epirubicin induced prominent swelling and crista damage of mitochondria and fragmentation of nuclei. Mitochondria were a normal size during a combination of epirubicin with either MPA- or tamoxifen treatment, despite the persistence of chromatin fragmentation and strong synergism on the clonogenic killing of breast tumor cells. Low dosage endocrine agent-induced anthracycline sensitization may be independent of mitochondrial toxicity. Further studies would be worthwhile, since the uncoupling of mitochondrial toxicity from the anti-neoplastic effect may also mean obviated cardiac toxicity in clinic.
Altinoz
Meric A
MA
Medical Biology and Genetics, Halic University, Institute of Health Halic Universitesi Merkez, Kampus Mecidiyekoy, Buyukdere Istanbul, Turkey, 34394 Istanbul, Turkey. maltinoz@gmail.com
Bilir
Ayhan
A
Gedikoglu
Gunduz
G
Ozcan
Emin
E
Oktem
Gulperi
G
Muslumanoglu
Mahmut
M
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D015251:Epirubicin / Q000633:toxicity*; D005260:Female; D006801:Humans; D007700:Kinetics; D008525:Medroxyprogesterone / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D013629:Tamoxifen / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D013629:Tamoxifen; D015251:Epirubicin; D008525:Medroxyprogesterone