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Antitumor Activities of 2-Methoxyestradiol on Cervical and Endometrial Cancers In Vitro and In Vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

2-Methoxyestradiol (2-ME), a metabolite of 17β-estradiol, is a potent antitumor and antiangiogenesis agent in vitro and in vivo. This study aimed to investigate the effects of 2-ME on human cervical and endometrial cancers in vitro and in vivo. Human cervical cancer HeLaS3 cells, endometrial cancer HEC-1-A and RL-95-2 cells, and severe combined immune deficient (SCID) mice were used. On cervical cancer HeLaS3 cells, 2-ME inhibited the cell growth which is accompanied by apoptosis via iNOS pathway and by G2/M cell cycle arrest. 2-ME had slight effects on normal cervical epithelial cells. In vivo on SCID mice, 2-ME (75 mg/kg p.o.) inhibited the growth of human cervical carcinoma by 34% (p < 0.05) and showed slight side effects to liver and spleen. On human endometrial cancer cells (HEC-1-A and RL-95-2 cells), 2-ME inhibited the growth by blocking cell cycle progress in S- and G2/M-phase in both cell types, and by inducing apoptosis in HEC-1-A cells and by causing necrosis in RL-95-2 cells. 2-ME had no effects on normal endometrial cells. The apoptotic effect, in HEC-1-A cells, was prevented by iNOS-inhibitor 1400W and eliminated by Caspase-inhibitor Z-VAD-FMK. The necrosis, on RL-95-2 cells, was due to a severe disruption of the mitochondrial membrane potential. Unfortunately, 2-ME had no significant effects on endometrial cancer xenografts. It showed slight toxicity to liver, spleen and proliferative effect on uterus. In conclusion, 2-ME inhibits the growth of human cervical and endometrial cancer cells in vitro. However, a weaker anti-tumor effect was observed in our animal model and 2-ME was slightly toxic to liver and spleen. Considering the proliferative effect on uterus, 2-ME might not be a suitable therapeutic agent in gynecological tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 62
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1374
Keywords [en]
Obstetrics and gynaecology, 2-Methoxyestradiol, HeLaS3 cells, HEC-1-A cells, RL-95-2 cells, cervical cancer, endometrial cancer
Keywords [sv]
Obstetrik och kvinnosjukdomar
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-4554ISBN: 91-554-6039-9 (print)OAI: oai:DiVA.org:uu-4554DiVA, id: diva2:165107
Public defence
2004-11-12, Rosénsalen, Ing 96, Kvinnokliniken, Akademiska sjukhuset, 751 85 Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-10-22 Created: 2004-10-22 Last updated: 2011-02-09Bibliographically approved
List of papers
1. Induction of apoptosis and G2/M arrest by 2-Methoxyestradiol in human cervical cancer HeLaS3 cells
Open this publication in new window or tab >>Induction of apoptosis and G2/M arrest by 2-Methoxyestradiol in human cervical cancer HeLaS3 cells
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2004 In: Anticancer Research, Vol. 24, no 2, p. 873-880Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92132 (URN)
Available from: 2004-10-22 Created: 2004-10-22Bibliographically approved
2. Antiproliferative activity and toxicity of 2-Methoxyestradiol in cervical cancer xenograft mice
Open this publication in new window or tab >>Antiproliferative activity and toxicity of 2-Methoxyestradiol in cervical cancer xenograft mice
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2005 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 15, no 2, p. 301-307Article in journal (Refereed) Published
Abstract [en]

2-methoxyestradiol (2-ME) is considered to be an effective anticancer compound for many types of tumors. We have previously demonstrated that 2-ME inhibits the growth of human cervical cancer HeLaS3 cells in vitro. In this study, we investigated the antitumoral effects of 2-ME on human cervical carcinoma in severe combined immune deficient (SCID) mice. The potential side effects of 2-ME on the SCID mice were also investigated. SCID mice were injected with HeLaS3 cells (3 x 10(6) to 4 x 10(6)/mouse) and a 15-day administration of 2-ME followed after a 1-week cell implantation. Tumor weight, volume, body weight, and blood chemistry were determined. Tumor tissues were examined with an antibody against the proliferative cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Liver, spleen, kidney, heart, and lung were screened by pathologic examinations. 2-ME (75 mg/kg p.o.) inhibited growth of human cervical carcinoma by 34% (P < 0.05) as compared with control. Necrosis was found in both 2-ME-treated and untreated tumor tissues, but the necrotic area was larger in 2-ME-treated mice. A low expression of proliferative cell nuclear antigen and an increased number of apoptotic cells were found in 2-ME-treated tumor sections as compared to those in controls. No significant difference was detected in blood chemistry. In addition, the liver showed hyperplastic Kupffer cells, hydropic swelling of hepatocytes, and liquefactive necrosis. The spleen showed an increased number of megakaryocytes and apoptotic cells after 2-ME treatment. Thus, 2-ME has an antitumor effect on human cervical carcinoma, and it is toxic to liver and spleen in this mouse model.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92133 (URN)15823116 (PubMedID)
Available from: 2004-10-22 Created: 2004-10-22 Last updated: 2017-12-14Bibliographically approved
3. Induction of apoptosis or necrosis in human endometrial cancer cells by 2-Methoxyestradiol
Open this publication in new window or tab >>Induction of apoptosis or necrosis in human endometrial cancer cells by 2-Methoxyestradiol
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2004 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 24, no 6, p. 3983-3990Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

We investigated the effects of 2methoxyestradiol (2-ME), an endogenous estrogenic metabolite, on human endometrial cancer HEC-1-A and RL-95-2 cell lines.

MATERIALS AND METHODS:

After exposure of HEC-1-A and RL-95-2 cells to 2-ME, the morphological changes were evaluated by acridine orange staining and transmission electron microscopy. Cell cycle progress, apoptosis and necrosis were assessed by flow cytometry, DNA fragmentation and Western blot.

RESULTS:

2-ME inhibited cell growth by blocking the S- and G2/M-phase in both cell lines, by inducing apoptosis in HEC-1-A cells and by causing necrosis in RL-95-2 cells. Apoptosis, on HEC-1-A cells, was accompanied by an increased expression of iNOS and STAT1. This apoptotic effect was prevented by the iNOS inhibitor 1400W and eliminated by the caspase inhibitor Z-VAD-FMK. Necrosis, on RL-95-2 cells, was due to a severe disruption of the mitochondrial membrane potential. 2-ME had no significant effect on normal human endometrial cells.

CONCLUSION:

The data suggest that 2-ME has an antitumor effect on human endometrial carcinoma cells (HEC-1-A and RL-95-2) and may contribute as a new therapeutic agent for endometrial cancer patients.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92134 (URN)15736443 (PubMedID)
Available from: 2004-10-22 Created: 2004-10-22 Last updated: 2017-12-14Bibliographically approved
4. Combinative effects of 2-Methoxyestradiol and arsenic trioxide in human endometrial cancer HEC-1-A cells
Open this publication in new window or tab >>Combinative effects of 2-Methoxyestradiol and arsenic trioxide in human endometrial cancer HEC-1-A cells
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92135 (URN)
Available from: 2004-10-22 Created: 2004-10-22Bibliographically approved
5. Effects of 2-methoxyestradiol on endometrial carcinoma xenografts
Open this publication in new window or tab >>Effects of 2-methoxyestradiol on endometrial carcinoma xenografts
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2007 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 133, no 5, p. 315-320Article in journal (Refereed) Published
Abstract [en]

Purpose: We have previously demonstrated that 2-methoxyestradiol (2-ME) inhibits the growth of human endometrial cancer HEC-1-A and RL-95-2 cells in vitro. In this study, we examined the effects of 2-ME on human endometrial carcinoma in severe combined immune deficient (SCID) mice. The potential side effects of 2-ME on SCID mice were also investigated. Methods: Severe combined immune deficient mice were injected with HEC-1-A cells (1 × 10 6/mouse) and a 18 day administration of 2-ME was followed after 1 week cell implantation. Tumor volume, weight, body weight and blood chemistry were determined. Tumor tissues were examined with an antibody against the proliferative cell nuclear antigen (PCNA) and Ki-67. Liver, spleen, kidney, heart, lung and uterus were screened by pathological examinations. Results: 2-ME (100 mg/kg p.o.) did not inhibit the growth of human endometrial carcinoma as compared to control. Necrotic areas were similar in both 2-ME-treated and -untreated tumor tissues. The expressions of PCNA and Ki-67 were similar in 2-ME-treated and untreated tumor sections. The wet weight of uterus was increased to more than threefold. The epithelial cells and glands in endometrium were increased. No significant difference was detected in blood AST, ALT and BUN. Conclusions: 2-ME has no antitumor effects on human endometrial carcinoma in our animal model. Its proliferative effects on endometrium and uterus might limit its use in gynecological cancers.

Keywords
2-Methoxyestradiol, Human endometrial carcinoma, SCID mice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92136 (URN)10.1007/s00432-006-0173-x (DOI)000245294700005 ()17165027 (PubMedID)
Available from: 2004-10-22 Created: 2004-10-22 Last updated: 2017-12-14Bibliographically approved

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