Limits...
"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.

Show MeSH

Related in: MedlinePlus

Inhibition of reductions of IL-18 and IFN-γ in sera and intestinal cells. Blood and intestinal samples were collected from the mice in the prevention when they were killed on days 29, 36 and 43. A,B: The serum levels of IL-18 (A) and IFN-γ (B) were measured in the above mice and a group of 6 healthy control mice. C: The intestinal tissues were sectioned, immunostained with Abs against mouse IL-18 and IFN-γ, respectively, and examined by microscopy. IL-18+ and IFN-γ+ cells were counted in 10 fields. Results are expressed as the mean value ± SD. “*” P < 0.05 and “**” P < 0.001 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen, and “‡” P < 0.05 versus the group fed the Fe-Lf diet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3539967&req=5

Figure 3: Inhibition of reductions of IL-18 and IFN-γ in sera and intestinal cells. Blood and intestinal samples were collected from the mice in the prevention when they were killed on days 29, 36 and 43. A,B: The serum levels of IL-18 (A) and IFN-γ (B) were measured in the above mice and a group of 6 healthy control mice. C: The intestinal tissues were sectioned, immunostained with Abs against mouse IL-18 and IFN-γ, respectively, and examined by microscopy. IL-18+ and IFN-γ+ cells were counted in 10 fields. Results are expressed as the mean value ± SD. “*” P < 0.05 and “**” P < 0.001 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen, and “‡” P < 0.05 versus the group fed the Fe-Lf diet.

Mentions: Blood samples were collected from the mice (n = 6, per group) sacrificed on days 29, 36 and 43 in the prevention experiment (Figure 2A). As shown in Figure 3A, mice bearing 4T1 tumors had significantly higher levels of serum IL-18 than the healthy control mice, at all the indicated time points. In contrast, the serum levels of IL-18 in mice fed the control diet and treated with tamoxifen were significantly (P < 0.05) lower on day 36 and 43 than those of untreated mice fed the control diet. Feeding of the Fe-Lf diet significantly (P < 0.05) elevated the serum IL-18 levels on days 29 and 36, compared to the control diet. The serum levels of IL-18 in mice treated with the combination of Fe-Lf diet and tamoxifen were significantly higher on day 29 (P < 0.01), 36 (P < 0.01) and 43 (P < 0.001) than those of mice treated with the combination of the control diet and tamoxifen. Serum levels of IFN-γ (Figure 3B) showed a similar pattern of change to IL-18, but the levels of serum IFN-γ in mice bearing 4T1 tumors were the similar to those in healthy controls, and did not significantly increase over time.


"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)

Inhibition of reductions of IL-18 and IFN-γ in sera and intestinal cells. Blood and intestinal samples were collected from the mice in the prevention when they were killed on days 29, 36 and 43. A,B: The serum levels of IL-18 (A) and IFN-γ (B) were measured in the above mice and a group of 6 healthy control mice. C: The intestinal tissues were sectioned, immunostained with Abs against mouse IL-18 and IFN-γ, respectively, and examined by microscopy. IL-18+ and IFN-γ+ cells were counted in 10 fields. Results are expressed as the mean value ± SD. “*” P < 0.05 and “**” P < 0.001 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen, and “‡” P < 0.05 versus the group fed the Fe-Lf diet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539967&req=5

Figure 3: Inhibition of reductions of IL-18 and IFN-γ in sera and intestinal cells. Blood and intestinal samples were collected from the mice in the prevention when they were killed on days 29, 36 and 43. A,B: The serum levels of IL-18 (A) and IFN-γ (B) were measured in the above mice and a group of 6 healthy control mice. C: The intestinal tissues were sectioned, immunostained with Abs against mouse IL-18 and IFN-γ, respectively, and examined by microscopy. IL-18+ and IFN-γ+ cells were counted in 10 fields. Results are expressed as the mean value ± SD. “*” P < 0.05 and “**” P < 0.001 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen, and “‡” P < 0.05 versus the group fed the Fe-Lf diet.
Mentions: Blood samples were collected from the mice (n = 6, per group) sacrificed on days 29, 36 and 43 in the prevention experiment (Figure 2A). As shown in Figure 3A, mice bearing 4T1 tumors had significantly higher levels of serum IL-18 than the healthy control mice, at all the indicated time points. In contrast, the serum levels of IL-18 in mice fed the control diet and treated with tamoxifen were significantly (P < 0.05) lower on day 36 and 43 than those of untreated mice fed the control diet. Feeding of the Fe-Lf diet significantly (P < 0.05) elevated the serum IL-18 levels on days 29 and 36, compared to the control diet. The serum levels of IL-18 in mice treated with the combination of Fe-Lf diet and tamoxifen were significantly higher on day 29 (P < 0.01), 36 (P < 0.01) and 43 (P < 0.001) than those of mice treated with the combination of the control diet and tamoxifen. Serum levels of IFN-γ (Figure 3B) showed a similar pattern of change to IL-18, but the levels of serum IFN-γ in mice bearing 4T1 tumors were the similar to those in healthy controls, and did not significantly increase over time.

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