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Exp Mol Pathol. 2014 Apr 26;97(1):6-15. doi: 10.1016/j.yexmp.2014.04.013. [Epub ahead of print]

In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer.

Author information

  • 1Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
  • 2Department of Comparative Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
  • 3Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
  • 4Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States. Electronic address: sdash@tulane.edu.

Abstract

The development of resistance to anticancer drugs is a major unsolved problem in the chemotherapy treatment of metastatic breast cancer. We have shown that increased expression of P-glycoprotein (P-gp) prevented nuclear entry of the doxorubicin molecules into murine breast cancer cells (4T1-R) leading to doxorubicin chemoresistance. This study was performed to test whether inhibition of P-gp using verapamil could overcome doxorubicin chemoresistance and eliminate multiorgan metastasis 4T1-R cells in BALB/c mouse. The 4T1-R cells were treated with doxorubicin alone, verapamil alone, and a combination of both. Multiorgan metastasis of 4T1-R cells in the presence and in the absence of combination treatment was determined in the BALB/c mouse model. Verapamil induced nuclear translocation of doxorubicin, G2-phase growth arrest and synergistically induced 100% cytotoxicity in 4T1-R cells in culture. However, the combination treatment using verapamil and doxorubicin did not improve the overall survival of BALB/c mice with metastatic breast cancer. Our results indicate that the combination treatment of verapamil and doxorubicin did not inhibit tumor growth in the lungs and liver indicating that the anticancer synergy mechanism of verapamil and doxorubicin is impaired in vivo in BALB/c mouse model with metastatic breast cancer. We propose that understanding the mechanisms as to why the combination of doxorubicin and verapamil treatment was impaired in the mouse model should allow novel approaches to improve chemotherapy response of metastatic breast cancer.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

4T1; Breast cancer; Chemoresistance; Chemotherapy; Doxorubicin; In vivo; Metastasis; Verapamil

PMID:
24780744
[PubMed - as supplied by publisher]
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