Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells.
BACKGROUND
Src family kinases control multiple cancer cell properties including cell cycle progression, survival, and metastasis. Recent studies suggest that the Src inhibitor dasatinib blocks these critical cancer cell functions.


METHODS
Because the molecular mechanism of action of dasatinib in breast cancers has not been investigated, we evaluated the effects of dasatinib as a single agent and in combination with the commonly used chemotherapeutic doxorubicin, on the proliferation, viability, and invasive capacity of breast cancer cells lines earlier categorised as dasatinib-sensitive (MDA-MB-231) and moderately resistant (MCF7 and T47D). We also tested the effects of these drugs on the actin cytoskeleton and associated signalling pathways.


RESULTS
The cell lines tested varied widely in sensitivity to growth inhibition (IC(50)=0.16-12.3 microM), despite comparable Src kinase inhibition by dasatinib (IC(50)=17-37 nM). In the most sensitive cell line, MDA-MB-231, dasatinib treatment induced significant G(1) accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P<0.01), and blocked the formation of invadopodia (P<0.001). Importantly, combination treatment with doxorubicin resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative MDA-MB-231 cell line.


CONCLUSIONS
The observed synergy between dasatinib and doxorubicin warrants the re-evaluation of dasatinib as an effective agent in multi-drug regimens for the treatment of invasive breast cancers.
Pichot
C S
CS
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, USA.
Hartig
S M
SM
Xia
L
L
Arvanitis
C
C
Monisvais
D
D
Lee
F Y
FY
Frost
J A
JA
Corey
S J
SJ
D000199:Actins / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069439:Dasatinib; D004317:Doxorubicin / Q000008:administration & dosage*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000199:Actins; D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014404:Tubulin; D004317:Doxorubicin; D019061:src-Family Kinases; D000069439:Dasatinib