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"Iron-saturated" bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice.

Sun X, Jiang R, Przepiorski A, Reddy S, Palmano KP, Krissansen GW - BMC Cancer (2012)

Bottom Line: The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies.Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors.The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1005, New Zealand.

ABSTRACT

Background: Tamoxifen is used in hormone therapy for estrogen-receptor (ER)-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf), a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers.

Methods: In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg) were fed an Fe-Lf supplemented diet (5 g/Kg diet) or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumor cell injection. Tumor growth, metastasis, body weight, and levels of interleukin 18 (IL-18) and interferon γ (IFN-γ) were analyzed.

Results: Tamoxifen weakly (IC(50) ~ 8 μM) inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors.

Conclusions: The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.

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Oral administration of Fe-Lf leads to high levels of Lf in leukocytes in the lamina propria and Peyer’s patches, which migrate to tumors. A,B: Identification of leukocyte subsets in the lamina propria (A) and Peyer’s patches (B) that contain high levels of Lf. Representative illustrations were taken on day 43 of intestinal villus and Peyer’s patch sections, respectively, from mice in the prevention experiment fed with control and Fe-Lf diets. Sections were immunostained with FITC-conjugated (green) Abs against bovine Lf. The anti-Lf Ab-stained intestinal villus sections were further stained with Abs against markers for macrophages, NK cells, T cells, B cells and dendritic cells. Illustrated are (A) intestinal sections double-stained with an anti-Lf Ab (green), and Abs (red) against macrophages and NK cells, and (B) Peyer’s patch sections double-stained with an anti-Lf Ab (green), and Abs (red) against T cells and B cells. Magnification, x200. Arrows point to the double-stained cells. The number of double-stained cells of each leukocyte subset was counted, and the percentage of each subset was calculated and plotted as a pie chart. C: Phenotyping of Lf-laden leukocytes that infiltrate the tumors of mice fed the Fe-Lf diet. Sections of tumors on day 29 taken from mice in the prevention experiment fed the control or Fe-Lf diets. Tumor sections were immunostained with a FITC-conjugated (green) anti-Lf Ab (left panel), followed by Abs (red) against leukocyte subset markers (right panel) for T cells, macrophages, B cells, NK cells and dendritic cells, as indicated.
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Figure 4: Oral administration of Fe-Lf leads to high levels of Lf in leukocytes in the lamina propria and Peyer’s patches, which migrate to tumors. A,B: Identification of leukocyte subsets in the lamina propria (A) and Peyer’s patches (B) that contain high levels of Lf. Representative illustrations were taken on day 43 of intestinal villus and Peyer’s patch sections, respectively, from mice in the prevention experiment fed with control and Fe-Lf diets. Sections were immunostained with FITC-conjugated (green) Abs against bovine Lf. The anti-Lf Ab-stained intestinal villus sections were further stained with Abs against markers for macrophages, NK cells, T cells, B cells and dendritic cells. Illustrated are (A) intestinal sections double-stained with an anti-Lf Ab (green), and Abs (red) against macrophages and NK cells, and (B) Peyer’s patch sections double-stained with an anti-Lf Ab (green), and Abs (red) against T cells and B cells. Magnification, x200. Arrows point to the double-stained cells. The number of double-stained cells of each leukocyte subset was counted, and the percentage of each subset was calculated and plotted as a pie chart. C: Phenotyping of Lf-laden leukocytes that infiltrate the tumors of mice fed the Fe-Lf diet. Sections of tumors on day 29 taken from mice in the prevention experiment fed the control or Fe-Lf diets. Tumor sections were immunostained with a FITC-conjugated (green) anti-Lf Ab (left panel), followed by Abs (red) against leukocyte subset markers (right panel) for T cells, macrophages, B cells, NK cells and dendritic cells, as indicated.

Mentions: We previously demonstrated that bovine Fe-Lf is taken up by cells residing in the lamina propria and Peyer’s patches [36]. In agreement, cells of the intestinal villi of mice fed the Fe-Lf diet contained high levels of Lf (Figure 4A), as compared to mice fed the control diet. Intestinal villus sections were double-stained with an Ab against bovine Lf and Abs against different leukocyte markers, followed by a FITC or alexa fluor 568-conjugated secondary Ab, respectively, to identify the cells that contained high levels of Lf. Representative illustrations show macrophages, and NK cells that contain high levels of Lf. The percentages of each leukocyte subset that had high levels of Lf were calculated (Figure 4A), indicating that macrophages, NK and T cells within the intestinal lamina propria contained the highest levels of Lf.


"Iron-saturated" bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice.

Sun X, Jiang R, Przepiorski A, Reddy S, Palmano KP, Krissansen GW - BMC Cancer (2012)

Oral administration of Fe-Lf leads to high levels of Lf in leukocytes in the lamina propria and Peyer’s patches, which migrate to tumors. A,B: Identification of leukocyte subsets in the lamina propria (A) and Peyer’s patches (B) that contain high levels of Lf. Representative illustrations were taken on day 43 of intestinal villus and Peyer’s patch sections, respectively, from mice in the prevention experiment fed with control and Fe-Lf diets. Sections were immunostained with FITC-conjugated (green) Abs against bovine Lf. The anti-Lf Ab-stained intestinal villus sections were further stained with Abs against markers for macrophages, NK cells, T cells, B cells and dendritic cells. Illustrated are (A) intestinal sections double-stained with an anti-Lf Ab (green), and Abs (red) against macrophages and NK cells, and (B) Peyer’s patch sections double-stained with an anti-Lf Ab (green), and Abs (red) against T cells and B cells. Magnification, x200. Arrows point to the double-stained cells. The number of double-stained cells of each leukocyte subset was counted, and the percentage of each subset was calculated and plotted as a pie chart. C: Phenotyping of Lf-laden leukocytes that infiltrate the tumors of mice fed the Fe-Lf diet. Sections of tumors on day 29 taken from mice in the prevention experiment fed the control or Fe-Lf diets. Tumor sections were immunostained with a FITC-conjugated (green) anti-Lf Ab (left panel), followed by Abs (red) against leukocyte subset markers (right panel) for T cells, macrophages, B cells, NK cells and dendritic cells, as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539967&req=5

Figure 4: Oral administration of Fe-Lf leads to high levels of Lf in leukocytes in the lamina propria and Peyer’s patches, which migrate to tumors. A,B: Identification of leukocyte subsets in the lamina propria (A) and Peyer’s patches (B) that contain high levels of Lf. Representative illustrations were taken on day 43 of intestinal villus and Peyer’s patch sections, respectively, from mice in the prevention experiment fed with control and Fe-Lf diets. Sections were immunostained with FITC-conjugated (green) Abs against bovine Lf. The anti-Lf Ab-stained intestinal villus sections were further stained with Abs against markers for macrophages, NK cells, T cells, B cells and dendritic cells. Illustrated are (A) intestinal sections double-stained with an anti-Lf Ab (green), and Abs (red) against macrophages and NK cells, and (B) Peyer’s patch sections double-stained with an anti-Lf Ab (green), and Abs (red) against T cells and B cells. Magnification, x200. Arrows point to the double-stained cells. The number of double-stained cells of each leukocyte subset was counted, and the percentage of each subset was calculated and plotted as a pie chart. C: Phenotyping of Lf-laden leukocytes that infiltrate the tumors of mice fed the Fe-Lf diet. Sections of tumors on day 29 taken from mice in the prevention experiment fed the control or Fe-Lf diets. Tumor sections were immunostained with a FITC-conjugated (green) anti-Lf Ab (left panel), followed by Abs (red) against leukocyte subset markers (right panel) for T cells, macrophages, B cells, NK cells and dendritic cells, as indicated.
Mentions: We previously demonstrated that bovine Fe-Lf is taken up by cells residing in the lamina propria and Peyer’s patches [36]. In agreement, cells of the intestinal villi of mice fed the Fe-Lf diet contained high levels of Lf (Figure 4A), as compared to mice fed the control diet. Intestinal villus sections were double-stained with an Ab against bovine Lf and Abs against different leukocyte markers, followed by a FITC or alexa fluor 568-conjugated secondary Ab, respectively, to identify the cells that contained high levels of Lf. Representative illustrations show macrophages, and NK cells that contain high levels of Lf. The percentages of each leukocyte subset that had high levels of Lf were calculated (Figure 4A), indicating that macrophages, NK and T cells within the intestinal lamina propria contained the highest levels of Lf.

Bottom Line: The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies.Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors.The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1005, New Zealand.

ABSTRACT

Background: Tamoxifen is used in hormone therapy for estrogen-receptor (ER)-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf), a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers.

Methods: In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg) were fed an Fe-Lf supplemented diet (5 g/Kg diet) or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumor cell injection. Tumor growth, metastasis, body weight, and levels of interleukin 18 (IL-18) and interferon γ (IFN-γ) were analyzed.

Results: Tamoxifen weakly (IC(50) ~ 8 μM) inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors.

Conclusions: The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.

Show MeSH
Related in: MedlinePlus