The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium.
Cancers of the reproductive tract account for 12% of all malignancies in women. As previous studies have shown that oestrogen metabolites can cause apoptosis, we characterised the effect of oestrogen and oestrogen metabolites on non-cancerous and cancerous human endometrial cells. Herein, we demonstrate that 2-methoxyoestradiol (2ME), but not 17beta-oestradiol, induces apoptosis in cancer cell lines and primary cultured tumours of endometrial origin. In contrast, 2ME had no effect on cell viability of corresponding normal tissue. This ability of 2ME to induce apoptosis does not require oestrogen receptor activation, but is associated with increased entry into the G2/M phases of the cell cycle and the activation of both the intrinsic and the extrinsic apoptotic pathways. The selective behaviour of 2ME on cancerous as opposed to normal tissue may be due to a reduction in 17beta-hydroxysteroid dehydrogenase type II levels in cancer cells and to a differential down-regulation of superoxide dismutase. Furthermore, we demonstrate that pre-treatment with 2ME enhances the sensitivity of reproductive tract cancer cells to the apoptotic drug tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), without the loss in cell viability to normal cells incurred by currently chemotherapeutic drugs. In conclusion, 2ME, alone or in combination with TRAIL, may be an effective treatment for cancers of uterine origin with minimal toxicity to corresponding healthy female reproductive tissue.
Kato
Sumie
S
Department of Obstetrics and Gynaecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Casilla 114-D, Chile.
Sadarangani
Anil
A
Lange
Soledad
S
Villalón
Manuel
M
Brañes
Jorge
J
Brosens
Jan J
JJ
Owen
Gareth I
GI
Cuello
Mauricio
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000201:enzymology*; D004717:Endometrium / Q000187:drug effects / Q000201:enzymology; D004964:Estriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004967:Estrogens; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C053615:2-methoxyestriol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D020169:Caspases; D004964:Estriol