In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer.
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.
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Michelle
M
McCarthy
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Gregory
G
Auda
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Suchi
S
Agrawal
Department of Comparative Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Amy
A
Taylor
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Zack
Z
Backstrom
Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Debasis
D
Mondal
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States.
Krzysztof
K
Moroz
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, United States. Electronic address: sdash@tulane.edu.
Srikanta
S
Dash
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D014700:Verapamil
4T1; Breast cancer; Chemoresistance; Chemotherapy; Doxorubicin; In vivo; Metastasis; Verapamil