Limits...
Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines.

Liem AA, Appleyard MV, O'Neill MA, Hupp TR, Chamberlain MP, Thompson AM - Br. J. Cancer (2003)

Bottom Line: Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission.Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity.These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Dundee, Dundee, UK.

ABSTRACT
In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.

Show MeSH

Related in: MedlinePlus

Western blot showing MAPK activity in MDA-MB-468 (A) and MCF-7 (B) breast cancer cell lines treated with doxorubicin (IC50) and vinorelbine (IC50) at different time points. Lane 1 shows untreated cells (control); lanes 2 and 3 represent doxorubicin control (4 h) and pretreatment with doxorubicin followed by vinorelbine; Lanes 4 and 5 show doxorubicin and vinorelbine control for the combined doxorubicin and vinorelbine treatment which is shown in lane 6; lanes 7 and 8 show doxorubicin control and vinorelbine pretreatment respectively. The MAPK activity was determined as previously described.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2747573&req=5

fig1: Western blot showing MAPK activity in MDA-MB-468 (A) and MCF-7 (B) breast cancer cell lines treated with doxorubicin (IC50) and vinorelbine (IC50) at different time points. Lane 1 shows untreated cells (control); lanes 2 and 3 represent doxorubicin control (4 h) and pretreatment with doxorubicin followed by vinorelbine; Lanes 4 and 5 show doxorubicin and vinorelbine control for the combined doxorubicin and vinorelbine treatment which is shown in lane 6; lanes 7 and 8 show doxorubicin control and vinorelbine pretreatment respectively. The MAPK activity was determined as previously described.

Mentions: The MDA-MB-468 and MCF-7 breast cancer cell lines showed constitutive MAPK and p38 activation (Figure 1Figure 1


Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines.

Liem AA, Appleyard MV, O'Neill MA, Hupp TR, Chamberlain MP, Thompson AM - Br. J. Cancer (2003)

Western blot showing MAPK activity in MDA-MB-468 (A) and MCF-7 (B) breast cancer cell lines treated with doxorubicin (IC50) and vinorelbine (IC50) at different time points. Lane 1 shows untreated cells (control); lanes 2 and 3 represent doxorubicin control (4 h) and pretreatment with doxorubicin followed by vinorelbine; Lanes 4 and 5 show doxorubicin and vinorelbine control for the combined doxorubicin and vinorelbine treatment which is shown in lane 6; lanes 7 and 8 show doxorubicin control and vinorelbine pretreatment respectively. The MAPK activity was determined as previously described.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747573&req=5

fig1: Western blot showing MAPK activity in MDA-MB-468 (A) and MCF-7 (B) breast cancer cell lines treated with doxorubicin (IC50) and vinorelbine (IC50) at different time points. Lane 1 shows untreated cells (control); lanes 2 and 3 represent doxorubicin control (4 h) and pretreatment with doxorubicin followed by vinorelbine; Lanes 4 and 5 show doxorubicin and vinorelbine control for the combined doxorubicin and vinorelbine treatment which is shown in lane 6; lanes 7 and 8 show doxorubicin control and vinorelbine pretreatment respectively. The MAPK activity was determined as previously described.
Mentions: The MDA-MB-468 and MCF-7 breast cancer cell lines showed constitutive MAPK and p38 activation (Figure 1Figure 1

Bottom Line: Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission.Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity.These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Dundee, Dundee, UK.

ABSTRACT
In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.

Show MeSH
Related in: MedlinePlus