Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer.

Abstract

BACKGROUND:

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).

METHODS:

TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues.

RESULTS:

Noscapine inhibited growth of MDA-MB-231 and MDA-MB-468 cells with the IC(50) values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150-550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.

CONCLUSIONS:

Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC.

• Authors: Mahavir B Chougule, Apurva R Patel, Tanise Jackson, Mandip Singh
• Journal: PloS one (PLoS One) Vol. 6 Issue 3 Pg. e17733 (Mar 15 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21423660 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inducing Agents
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• NF-kappa B
• Doxorubicin
• Noscapine
• Caspase 3

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Breast Neoplasms (blood supply, drug therapy, enzymology, pathology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Fragmentation (drug effects)
• Doxorubicin (pharmacology, therapeutic use)
• Drug Synergism
• Female
• Humans
• Immunohistochemistry
• Mice
• NF-kappa B (metabolism)
• Neovascularization, Pathologic (drug therapy, pathology)
• Noscapine (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays