Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination

Abstract

This study examined whether suppression of mammary gland carcinogenesis elicited by low doses of tamoxifen (TAM) can be enhanced by concomitant treatment of rats with indole-3-carbinol (I3C), a component of cruciferous vegetables and a dietary supplement used for its putative antiestrogenicity. Two weeks after one oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 65 mg/kg body weight, female Sprague-Dawley rats started treatment with TAM (10 microg/rat) by subcutaneous injection, I3C (250 mg/kg body weight) by oral gavage, TAM+I3C or their respective vehicles three times per week, for up to 20 weeks. Significant increases in the median latency of malignant mammary tumors and decreases in the mean tumor mass per rat were due to TAM. Significant decreases in the mean tumor number per rat in TAM, I3C and TAM+I3C-treated rats indicated a cooperative effect of the two compounds. In both DMBA-initiated and uninitiated rats, significant increases in the ratios of liver to body weight in I3C and TAM+I3C-treated groups coincided with I3C-dependent increases of hepatic cytochrome P450 levels and activities (1A1, 1A2 and 2B1/2). The ratios of uterus to body weight decreased with the number of treatments and the decreases effected by TAM were greater than those by I3C. The levels of circulating estrone were increased in response to I3C treatment and were greater in DMBA-initiated rats than in uninitiated rats, which may contribute to the preventive effect of I3C. Chemoprevention may be accomplished through up-regulation of apoptotic enzyme (caspase) activities in the mammary gland or mammary tumors. Treatment with TAM, I3C or TAM+I3C had no effect on caspase-3&7, caspase-6, caspase-8 and caspase-9 activities in the mammary tumors or mammary gland of tumor-bearing rats or that of uninitiated rats. In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities, suggesting an I3C-mediated protective effect. Even though I3C alone is a much less effective suppressing agent of mammary carcinogenesis than TAM, I3C in combination with TAM does not weaken but may foster the benefits of chemoprevention with TAM.

Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Women’s Healthy Eating and Living Study

“…Second, indole-3-carbinol (I3C) ? tamoxifen in combination have been associated with a fourfold reduction in DMBA-induced mammary tumors in rats, a response that was accompanied by prolonged tumor latency [18]. Finally, a study in Fisher rats showed diindolylmethane (DIM), the major metabolic end-product of indole-3-carbinol, down-regulated flavincontaining monooxygenase activity (FMO) in liver tissue [29] and when co-administered with tamoxifen resulted in an inhibition in tamoxifen N-oxide.…”

“…We postulated that any dietary effects on recurrent disease might differ in the presence or absence of tamoxifen given the profound effects of tamoxifen in reducing the risk of recurrent disease [17]. In addition, existing mechanistic evidence is suggestive for a synergistic anti-carcinogenic action of combinational interventions with selected bioactive constituents in cruciferous and tamoxifen as well as estrogen receptor alpha [18][19][20]. This led us also to evaluate the independent associations between cruciferous vegetable intake and recurrent disease risk among women taking tamoxifen.…”

Indole-3-carbinol enhances anti-proliferative, but not anti-invasive effects of oxaliplatin in colorectal cancer cell lines

“…In recent years, a few studies have hinted at the potential for I3C to enhance chemotherapeutic regimes [12,29,30]. Yet to date, combinatorial options remain largely unexplored.…”

Efeitos morfológicos, histológicos e moleculares dos moduladores seletivos dos receptores de estrogênios tamoxifeno e raloxifeno na prevenção primária de tumores mamários quimicamente induzidos em ratas

“…Dessa forma, o estudo de substâncias quimioprotetoras, como os SERMs tamoxifeno, raloxifeno e outros são cada vez mais usados (Russo et al 1990(Russo et al , 2005aLuo et al, 1998;Barros et al, 2003;El-Bayoumi e Sinha, 2004;Kim et al, 2004;Manjanatha et al, 2006;Stuhr et al, 2006;Malejka-Giganti et al, 2007).…”

“…Nossos resultados revelaram receptor hormonal positivo para os três grupos estudados (DMBA, raloxifeno e tamoxifeno), evidenciando que as diferenças encontradas, para esse modelo animal, devem-se à ação dos SERMs (Russo et al, 2005a;Manjanatha et al, 2006;Stuhr et al, 2006;Malejka-Giganti et al, 2007); não havendo diferença estatística quanto a esse paramêtro.…”