Limits...
Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines.

Ozbay T, Nahta R - Breast Cancer (Auckl) (2011)

Bottom Line: Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables.MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin.In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology.

ABSTRACT
Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.

No MeSH data available.


Related in: MedlinePlus

Delphinidin reduces anti-proliferative activity of HER2-targeted therapies: potential for drug antagonism. (A) BT474 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (B) BT474 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. (C) SKBR3 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (D) SKBR3 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. Control cells were treated with DMSO at the volume found in the highest concentration of delphinidin and/or lapatinib. After 6 d, MTS colorimetric assays were performed to measure cell proliferation.Notes: Values are expressed as a percentage of control DMSO group per line. Error bars represent standard deviation between six replicates. Statistical significance of differences between treatment groups was determined by ANOVA; ##P<0.005. Statistical significance of each treatment versus control was determined per cell line by student’s t-test; *P ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3140266&req=5

f5-bcbcr-5-2011-143: Delphinidin reduces anti-proliferative activity of HER2-targeted therapies: potential for drug antagonism. (A) BT474 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (B) BT474 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. (C) SKBR3 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (D) SKBR3 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. Control cells were treated with DMSO at the volume found in the highest concentration of delphinidin and/or lapatinib. After 6 d, MTS colorimetric assays were performed to measure cell proliferation.Notes: Values are expressed as a percentage of control DMSO group per line. Error bars represent standard deviation between six replicates. Statistical significance of differences between treatment groups was determined by ANOVA; ##P<0.005. Statistical significance of each treatment versus control was determined per cell line by student’s t-test; *P ≤ 0.05.

Mentions: Our initial data suggested that delphinidin inhibits HER2 signaling. Since delphinidin is a major bioactive component of some complementary cancer medicines, we examined the effect of combining delphinidin with the currently approved HER2-targeted drugs Herceptin and lapatinib in BT474 and SKBR3 HER2-overexpressing breast cancer cells. Low doses of delphinidin (6, 12, or 24 μg/mL) and clinically relevant concentrations of Herceptin (5, 10, or 20 μg/mL) and lapatinib (100, 200, or 400 nM) were used in these studies. MTS proliferation assays showed that BT474 and SKBR3 cells were sensitive to Herceptin and lapatinib, but that addition of delphinidin did not further inhibit proliferation (Fig. 5). Instead, addition of delphinidin significantly reduced the anti-proliferative effect of Herceptin in BT474 (Fig. 5A) and SKBR3 (Fig. 5C) cell lines. Similarly, delphinidin reduced the anti-proliferative activity of lapatinib in BT474 (Fig. 5B) and SKBR3 (Fig. 5D). Thus, there was not any apparent benefit to adding delphinidin to HER2-targeted therapy; rather, delphinidin appeared to actually reduce efficacy of these approved breast cancer drugs. Thus, while single agent delphinidin showed activity in breast cancer cell lines, combination with currently approved targeted therapies must be examined closely to avoid potential drug antagonism.


Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines.

Ozbay T, Nahta R - Breast Cancer (Auckl) (2011)

Delphinidin reduces anti-proliferative activity of HER2-targeted therapies: potential for drug antagonism. (A) BT474 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (B) BT474 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. (C) SKBR3 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (D) SKBR3 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. Control cells were treated with DMSO at the volume found in the highest concentration of delphinidin and/or lapatinib. After 6 d, MTS colorimetric assays were performed to measure cell proliferation.Notes: Values are expressed as a percentage of control DMSO group per line. Error bars represent standard deviation between six replicates. Statistical significance of differences between treatment groups was determined by ANOVA; ##P<0.005. Statistical significance of each treatment versus control was determined per cell line by student’s t-test; *P ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140266&req=5

f5-bcbcr-5-2011-143: Delphinidin reduces anti-proliferative activity of HER2-targeted therapies: potential for drug antagonism. (A) BT474 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (B) BT474 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. (C) SKBR3 cells were treated with 5, 10, or 20 μg/mL Herceptin (HCT), 6, 12, or 24 μg/mL delphinidin (delph), or combination HCT + delph. (D) SKBR3 cells were treated with 100, 200, or 400 nM lapatinib (lap), 6, 12, or 24 μg/mL delphinidin (delph), or combination lap + delph. Control cells were treated with DMSO at the volume found in the highest concentration of delphinidin and/or lapatinib. After 6 d, MTS colorimetric assays were performed to measure cell proliferation.Notes: Values are expressed as a percentage of control DMSO group per line. Error bars represent standard deviation between six replicates. Statistical significance of differences between treatment groups was determined by ANOVA; ##P<0.005. Statistical significance of each treatment versus control was determined per cell line by student’s t-test; *P ≤ 0.05.
Mentions: Our initial data suggested that delphinidin inhibits HER2 signaling. Since delphinidin is a major bioactive component of some complementary cancer medicines, we examined the effect of combining delphinidin with the currently approved HER2-targeted drugs Herceptin and lapatinib in BT474 and SKBR3 HER2-overexpressing breast cancer cells. Low doses of delphinidin (6, 12, or 24 μg/mL) and clinically relevant concentrations of Herceptin (5, 10, or 20 μg/mL) and lapatinib (100, 200, or 400 nM) were used in these studies. MTS proliferation assays showed that BT474 and SKBR3 cells were sensitive to Herceptin and lapatinib, but that addition of delphinidin did not further inhibit proliferation (Fig. 5). Instead, addition of delphinidin significantly reduced the anti-proliferative effect of Herceptin in BT474 (Fig. 5A) and SKBR3 (Fig. 5C) cell lines. Similarly, delphinidin reduced the anti-proliferative activity of lapatinib in BT474 (Fig. 5B) and SKBR3 (Fig. 5D). Thus, there was not any apparent benefit to adding delphinidin to HER2-targeted therapy; rather, delphinidin appeared to actually reduce efficacy of these approved breast cancer drugs. Thus, while single agent delphinidin showed activity in breast cancer cell lines, combination with currently approved targeted therapies must be examined closely to avoid potential drug antagonism.

Bottom Line: Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables.MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin.In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology.

ABSTRACT
Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.

No MeSH data available.


Related in: MedlinePlus