Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-01, Vol.65 (2), p.387-393
• Main Authors: HAN, Gui-Zhen, LIU, Zhi-Jian, SHIMOI, Kayoko, BAO TING ZHU
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Doxorubicin - administration & dosage; Drug Synergism; Estradiol - administration & dosage; Estradiol - analogs & derivatives; Estradiol - pharmacology; Female; Fluorouracil - administration & dosage; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Tumors; Vinblastine - administration & dosage; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.387.65.2

2-Methoxyestradiol (2-MeO-E(2)), a well-known nonpolar endogenous metabolite of 17beta-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions in vitro and in vivo at pharmacologic concentrations. We determined in the present study whether 2-MeO-E(2) can enhance the anticancer actions of paclitaxel or vinorelbine (two commonly used microtubule-disrupting agents) in several human breast cancer cell lines, including the estrogen receptor-positive MCF-7 and T-47D cells and the receptor-negative MDA-MB-435s and MDA-MB-231 cells. 2-MeO-E(2) in combination with paclitaxel or vinorelbine exhibited a synergistic anticancer effect in these human breast cancer cells in vitro, and this synergistic effect was more pronounced when each of the drugs was used at relatively low concentrations. Additional experiments using female athymic BALB/c nu/nu mice showed that p.o. administration of 2-MeO-E(2) at 30 mg/kg body weight, once a week for 6 weeks, markedly enhanced the activity of paclitaxel or vinorelbine against the growth of the estrogen receptor-negative MDA-MB-231 human breast cancer xenografts in these animals. By contrast, combination of 2-MeO-E(2) with 5-fluorouracil only had a partial additive effect against the growth of these cell lines in culture, and no synergistic effect was observed. Interestingly, when doxorubicin was used in combination with 2-MeO-E(2), the antiproliferative effect of 2-MeO-E(2) was somewhat antagonized by doxorubicin when it was present at high concentrations. Our results showed that 2-MeO-E(2) at nontoxic or subtoxic doses selectively enhanced the effects of certain microtubule-disrupting agents (such as paclitaxel and vinorelbine) against the growth of the receptor-negative human breast cancer cells in culture and also in athymic nude mice.