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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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Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors and their metastasis to livers and lungs. A,B: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors. A: In the prevention experiment, 6 mice from each group were randomly killed for sampling on days 29, 36, and 43 following placement on diets and the start of administration of tamoxifen (TAM). Tumor size was measured every two days. B: In the treatment experiment, tamoxifen (TAM) was administered to the mice 14 days after injection of tumor cells. Each group had 6 mice, and tumor size was measured every two days. C,D: Fe-Lf augments tamoxifen therapy to suppress metastasis to livers and lungs. Mice in the prevention experiment were euthanized on day 43, and their livers and lungs removed. The livers were sectioned and stained with HE. The numbers of metastatic tumor nodules in liver sections (C) and the number of metastatic tumors on the surface of lungs (D) were counted, respectively. Results are expressed as the mean value ± SD. “*” P < 0.05 or “**” 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. E: Fe-Lf attenuates loss of body weight caused by cancer cachexia and tamoxifen therapy, and inhibits tamoxifen-induced reductions of IL-18 and IFN-γ in sera and intestinal cells. The mice in the prevention experiment were weighed every two days. “*” P < 0.05 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen (TAM).
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Figure 2: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors and their metastasis to livers and lungs. A,B: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors. A: In the prevention experiment, 6 mice from each group were randomly killed for sampling on days 29, 36, and 43 following placement on diets and the start of administration of tamoxifen (TAM). Tumor size was measured every two days. B: In the treatment experiment, tamoxifen (TAM) was administered to the mice 14 days after injection of tumor cells. Each group had 6 mice, and tumor size was measured every two days. C,D: Fe-Lf augments tamoxifen therapy to suppress metastasis to livers and lungs. Mice in the prevention experiment were euthanized on day 43, and their livers and lungs removed. The livers were sectioned and stained with HE. The numbers of metastatic tumor nodules in liver sections (C) and the number of metastatic tumors on the surface of lungs (D) were counted, respectively. Results are expressed as the mean value ± SD. “*” P < 0.05 or “**” 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. E: Fe-Lf attenuates loss of body weight caused by cancer cachexia and tamoxifen therapy, and inhibits tamoxifen-induced reductions of IL-18 and IFN-γ in sera and intestinal cells. The mice in the prevention experiment were weighed every two days. “*” P < 0.05 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen (TAM).

Mentions: Groups of Balb/c mice were placed on either the control diet or the Fe-Lf diet, and received injections of either PBS or tamoxifen every two days to determine whether Fe-Lf would augment the effects of tamoxifen in preventing the formation of breast tumors (Figure 1A). Fourteen days after starting the treatments, 4T1 breast tumor cells were injected into the right inguinal mammary fat pad. Neither the Fe-Lf nor tamoxifen monotherapies delayed the appearance of palpable 4T1 tumors, whereas in contrast the combination of the Fe-Lf diet and tamoxifen delayed the appearance of palpable tumors by 4 days, and inhibited their growth compared with the control diet (Figure 2A). Consequently, on day 43 the tumors formed were on average 48% smaller (P < 0.001) than the tumors in the control diet group, and were significantly (P < 0.05) smaller than tumors of the monotherapy groups (Figure 2A). Nevertheless, each of the Fe-Lf and tamoxifen monotherapies inhibited tumor growth, resulting in significantly (both P < 0.05) smaller tumors on day 43 than the tumors of mice fed the control diet. The size of tumors was in accordance with the weight of tumors as shown in Table 2. To investigate whether the effects of the combination of the Fe-Lf diet and tamoxifen were synergistic, we calculated the value for the coefficient of drug interaction (CDI), as described previously [40]. The CDI value on day 43 was 0.9 (less than 1), indicating that Fe-Lf and tamoxifen have a synergistic effect in inhibiting tumor growth.


"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)

Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors and their metastasis to livers and lungs. A,B: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors. A: In the prevention experiment, 6 mice from each group were randomly killed for sampling on days 29, 36, and 43 following placement on diets and the start of administration of tamoxifen (TAM). Tumor size was measured every two days. B: In the treatment experiment, tamoxifen (TAM) was administered to the mice 14 days after injection of tumor cells. Each group had 6 mice, and tumor size was measured every two days. C,D: Fe-Lf augments tamoxifen therapy to suppress metastasis to livers and lungs. Mice in the prevention experiment were euthanized on day 43, and their livers and lungs removed. The livers were sectioned and stained with HE. The numbers of metastatic tumor nodules in liver sections (C) and the number of metastatic tumors on the surface of lungs (D) were counted, respectively. Results are expressed as the mean value ± SD. “*” P < 0.05 or “**” 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. E: Fe-Lf attenuates loss of body weight caused by cancer cachexia and tamoxifen therapy, and inhibits tamoxifen-induced reductions of IL-18 and IFN-γ in sera and intestinal cells. The mice in the prevention experiment were weighed every two days. “*” P < 0.05 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen (TAM).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539967&req=5

Figure 2: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors and their metastasis to livers and lungs. A,B: Fe-Lf augments tamoxifen therapy to suppress the formation and growth of 4T1 tumors. A: In the prevention experiment, 6 mice from each group were randomly killed for sampling on days 29, 36, and 43 following placement on diets and the start of administration of tamoxifen (TAM). Tumor size was measured every two days. B: In the treatment experiment, tamoxifen (TAM) was administered to the mice 14 days after injection of tumor cells. Each group had 6 mice, and tumor size was measured every two days. C,D: Fe-Lf augments tamoxifen therapy to suppress metastasis to livers and lungs. Mice in the prevention experiment were euthanized on day 43, and their livers and lungs removed. The livers were sectioned and stained with HE. The numbers of metastatic tumor nodules in liver sections (C) and the number of metastatic tumors on the surface of lungs (D) were counted, respectively. Results are expressed as the mean value ± SD. “*” P < 0.05 or “**” 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. E: Fe-Lf attenuates loss of body weight caused by cancer cachexia and tamoxifen therapy, and inhibits tamoxifen-induced reductions of IL-18 and IFN-γ in sera and intestinal cells. The mice in the prevention experiment were weighed every two days. “*” P < 0.05 versus the group fed the control diet, “†” P < 0.05 versus the group fed the control diet and treated with tamoxifen (TAM).
Mentions: Groups of Balb/c mice were placed on either the control diet or the Fe-Lf diet, and received injections of either PBS or tamoxifen every two days to determine whether Fe-Lf would augment the effects of tamoxifen in preventing the formation of breast tumors (Figure 1A). Fourteen days after starting the treatments, 4T1 breast tumor cells were injected into the right inguinal mammary fat pad. Neither the Fe-Lf nor tamoxifen monotherapies delayed the appearance of palpable 4T1 tumors, whereas in contrast the combination of the Fe-Lf diet and tamoxifen delayed the appearance of palpable tumors by 4 days, and inhibited their growth compared with the control diet (Figure 2A). Consequently, on day 43 the tumors formed were on average 48% smaller (P < 0.001) than the tumors in the control diet group, and were significantly (P < 0.05) smaller than tumors of the monotherapy groups (Figure 2A). Nevertheless, each of the Fe-Lf and tamoxifen monotherapies inhibited tumor growth, resulting in significantly (both P < 0.05) smaller tumors on day 43 than the tumors of mice fed the control diet. The size of tumors was in accordance with the weight of tumors as shown in Table 2. To investigate whether the effects of the combination of the Fe-Lf diet and tamoxifen were synergistic, we calculated the value for the coefficient of drug interaction (CDI), as described previously [40]. The CDI value on day 43 was 0.9 (less than 1), indicating that Fe-Lf and tamoxifen have a synergistic effect in inhibiting tumor growth.

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