Anti‐breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions

Abstract

Long-term treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. Several antiestrogens developed in last decades have been discontinued from clinical testing because of their undesirable effects on the uterus. To avoid such serious side-effect while increasing the drug's anti-breast cancer potential, new triphenylethylene antiestrogens, 2E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and 2E-3-{4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenyl}acrylic acid (SS1010), were designed as safer alternatives. Unlike TAM, SS1020 does not present significant uterotrophic potential in rats; in contrast, SS1010, a compound removing a 4-OH moiety from SS1020, represented weak uterotrophic activity. The structurally related compounds 4-hydroxytamoxifen, toremifene, ospemifene, raloxifene (RAL) and GW5638 all have uterotrophic activity. In addition, SS1020 and SS1010 exhibit no genotoxic activity to damage hepatic DNA in rats. Therefore, SS1020 was selected as a safer antiestrogen candidate and used for evaluating the antitumor potential in animals. At the human equivalent doses of TAM, SS1020 had antitumor potential much higher than that of TAM, RAL and GW5638 against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS1020. SS1020, lacking estrogenic and genotoxic actions and having strong antitumor potency superior to that of TAM and RAL, could be a safer alternative for breast cancer therapy and prevention.Tamoxifen (TAM; the structure is given in Fig. 1a) is widely used as a first-line endocrine therapy for breast cancer patients with positive estrogen receptors (ER) 1 and as a prophylactic agent for women at high risk of developing this disease. 2 Besides the significant benefit, long-term administration of TAM has serious adverse effects, including endometrial cancer in women. [2][3][4] The carcinogenic effect is thought to involve initiation and/or promotion due to TAM-induced DNA damage as well as the drug's estrogenic action (reviewed in Refs. 5, 6). TAM and its metabolites are a-hydroxylated and undergo Osulfonation catalyzed by hydroxysteroid sulfotransferase, after which they react with guanine residues in cellular DNA, forming TAM-DNA adducts. 5 TAM-DNA adducts were detected in the liver of rodents treated with TAM, 7,8 in several tissues, including the ovary and uterus of monkeys, 9 and in the endometrium of certain women receiving TAM. 10,11 K-ras mutations were detected frequently in the endometria of women treated with TAM. 12 Because TAM-DNA adducts are highly mutagenic 13 and not rapidly repaired, 14 the DNA adducts may contribute to the initiation of endometrial cancer. Like estrogens, TAM is a partial ER agonist in uterine tissue 15 ; such estrogenic effects may also contribute to promoting endometrial cancer. 16 Therefore, TAM alternatives free of genotoxic and estrogenic potential are required t...

Anti-breast cancer potential of daidzein in rodents

“…In our previous papers (Laxmi et al, 2010;Suzuki et al, 2011), DMBA-induced mammary tumors were confirmed by pathological examination. The sections of the mammary tumors were deparaffinized in xylene and processed routinely and stained with hematoxylin and eosin.…”

“…Rats were given water and a phytoestrogen-free AIN-76A diet food and kept on a 12 h light/dark cycle throughout the study. Mammary carcinoma (~8 mm diameter tumor) was induced by treating rats (Sprague-Dawley, 8-week-old females) with a single oral dose (50 mg/kg) of DMBA, following the established protocol (Toko et al, 1995;Yamamoto et al, 2005;Laxmi et al, 2010;Suzuki et al, 2011). The rats (5 rats/dose) were then treated orally for 3 weeks with daidzein (0.69 or 6.9 mg/kg/day), equol (0.65 mg/kg/day), genistein (0.73 mg/kg/day), or TAM (1.0 mg/kg/day) at a dose molar equivalent to TAM [1.0 mg (2.7 μmol)/kg or 10 mg (27 μmol)/kg/day].…”

“…Mice supplemented with an E 2 (0.72 mg) pellet were injected with MCF-7 cells (4×10 7 cells) s.c. into the shoulder region, following an established protocol (Willson et al, 1997;Laxmi et al, 2010;Suzuki et al, 2011); the tumors (up to~6 mm in diameter) were allowed to grow for 4 weeks. The nude mice (4-5 mice/dose) were then treated orally for 4 weeks with daidzein (6.9 mg/kg/day) or genistein (7.3 mg/kg/day) at a dose molar equivalent to TAM [10 mg (27 μmol)/kg/day].…”

“…To investigate the anti-breast cancer potential against human breast cancer xenografts, compounds such as antiestrogen were treated to ovariectomized (OVX)-athymic nude mice implanted with an E 2 -pellet (Toko et al, 1995;Yamamoto et al, 2005;Laxmi et al, 2010;Suzuki et al, 2011). However, in several reports by Helferich and his colleagues (Hsieh et al, 1998;Allred et al, 2001aAllred et al, ,2001bJu et al, 2001Ju et al, , 2006aJu et al, ,2006b, dietary isoflavone was given to OVX-mice after removal of the implanted E 2 -pellet.…”

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

“…31,32 Several novel SERMs have been synthesized and evaluated for their potential to improve breast cancer treatment with reduced adverse effect profile compared to the gold-standard TAM. [33][34][35] Collectively, the results of these studies demonstrate that the CYP2D6-generated 4-OH metabolites of TAM represent a much higher percentage of total plasma exposure with TAM treatment, and at many-fold greater estrogenic and antiestrogenic activity, these active TAM metabolites are likely to measurably contribute to the clinical efficacy and safety profile of TAM in women with breast cancer. Adjusted for dose, the plasma concentrations of TOR and metabolites reported in our study are consistent with the values for the 60 mg clinical dose reported in previous studies.…”