RU 58668: Further in vitro and in vivo pharmacological data related to its antitumoral activity

Velde, P. van de; Nique, F.; Planchon, P.; Prevost, Grégoire; Brëmaud, J.; Hameau, M. C.; Magnien, V.; Philibert, D.; Teutsch, G.

doi:10.1016/s0960-0760(96)00140-9

Cited by 32 publications

(25 citation statements)

References 14 publications

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“…In males, testosterone propionate at 10 mg/kg/d was administered by daily subcutaneous injection, and in females, a lower dose of 2.5 mg/kg/d was administered by slow-release pellet (Innovative Research of America). Antiestrogen RU58668 (19) and antiandrogens RU58642 and RU50818 (20,21) were administered at 10 mg/kg/d and 30 mg/kg/d, respectively, by daily subcutaneous injection.…”

Section: Methodsmentioning

confidence: 99%

A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Sims¹,

Clément-Lacroix²,

Minet³

et al. 2003

J. Clin. Invest.

170

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Although the role of estradiol in maintaining bone mass is well established, the relative contributions of the estradiol receptors ERα and ERβ and of the androgen receptor (AR) remain controversial. To determine the role of ERα-mediated, ERβ-mediated, and non–ER-mediated mechanisms in maintaining bone mass, gonadectomy and estradiol treatment were studied in ER-knockout mice. Estradiol treatment of ovariectomized ERαβ–/– mice failed to prevent bone loss, precluding significant effects of estradiol on bone through non–ER-signaling pathways. In contrast, estradiol prevented ovariectomy-induced bone loss in ERβ–/– mice, as in WT males and females, indicating that ERα is the major mediator of estradiol effects in bone. No response of bone to estradiol was detected in orchidectomized ERα–/– mice, suggesting estradiol cannot protect bone mass via the AR in vivo. In contrast to female ERαβ–/– and male ERα–/– mice, female ERα–/– mice were partially protected against ovariectomy-induced bone loss by estradiol, confirming that ERβ mediates estradiol effects in bone, but only in females and with a lower efficacy than ERα. We conclude that ERα is the main effector of estradiol’s protective function in bone in both male and female mice, and that, in its absence, AR is not sufficient to mediate this response

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Section: Methodsmentioning

confidence: 99%

A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Sims¹,

Clément-Lacroix²,

Minet³

et al. 2003

J. Clin. Invest.

170

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“…However, RU 58,668 was 30-50 times more potent than 4-OH-tamoxifen and 2.7-4.2 times more potent than ICI 182,780 with respect to inhibition of MCF-7 cell growth [2]. Importantly, RU 58,668 induced long-term regression of E2 stimulated MCF-7 xenografts implanted in athymic mice, whereas ICI 182,780 stabilized the tumor size and tamoxifen eventually stimulated the growth of the xenografts [13]. In addition, RU 58,668 was more effective than ICI 182,780 in inhibition of tamoxifen-resistant MCF-7 xenografts during an eightweek period [3].…”

Section: Introductionmentioning

confidence: 98%

Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668

Fog

Christensen

Lykkesfeldt

2005

Breast Cancer Res Treat

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Breast cancer is the most common cancer disease in women in the western world. Tamoxifen has been the standard first line endocrine therapy for patients with estrogen receptor (ER) positive tumors. Unfortunately, almost all patients with advanced disease develop tamoxifen resistance. This has lead to a search for new potent antiestrogens. One of the new compounds under development is the pure antiestrogen RU 58,668. To study the mechanisms behind acquired resistance to RU 58,668, the RU 58,668-resistant cell line MCF-7/RU58(R)-1 (RU58(R)-1) was developed. The RU58(R)-1 cell line was responsive to tamoxifen, but cross-resistant to ICI 182,780 and the estrogen-sensitivity was reduced compared to the parental MCF-7 cell line. The protein levels of ERalpha, IGF-I Receptor (IGF-IR) and Bcl-2 were severely reduced, when RU58(R)-1 cells were cultured with RU 58,668 and the expression of progesterone receptor (PR) was lost. The ERalpha level increased upon withdrawal of RU 58,668 and the ERalpha protein was destabilized by RU 58,668 in both cell lines. Regulation of most of the investigated estrogen-sensitive mRNAs was found to be normal in the resistant cells. The protein levels of IGF-IR, Bcl-2 and the IGF Binding Protein 2 (IGFBP2) reverted towards MCF-7 levels upon RU 58,668 withdrawal, but the resistant phenotype was maintained. Thus, it appears as acquired resistance to RU 58,668 is not a result of loss of the ERalpha expression or function and we suggest that in the presence of RU 58,668, the RU58(R)-1 cell line probably uses other mitogenic pathways than the ERalpha pathway for growth and survival.

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“…In our laboratory, we have developed cell lines with acquired antiestrogen resistance to several welldescribed antiestrogens: tamoxifen, ICI 164,384, ICI 182,780 and the very potent pure steroidal antiestrogen RU 58,668 (Lykkesfeldt et al 1994, Van de Velde et al 1996, Madsen et al 1997, Fog et al 2005. Our design for establishing resistant cell lines has been to adapt MCF-7 cells to grow with a low amount of fetal calf serum (FCS; 1%) containing estrogenic compounds corresponding to the level in the serum from postmenopausal women (Briand & Lykkesfeldt 1984).…”

Section: Introductionmentioning

confidence: 99%

Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

Frogne¹,

Jepsen²,

Larsen³

et al. 2005

Endocr Relat Cancer

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Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifenand an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

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RU 58668: Further in vitro and in vivo pharmacological data related to its antitumoral activity

Cited by 32 publications

References 14 publications

A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Characterization of a human breast cancer cell line, MCF-7/RU58R-1, resistant to the pure antiestrogen RU 58,668

Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

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