@Article{096504020X15898794315356,
AUTHOR = {Leonard Lothstein, Judith Soberman, Deanna Parke, Jatin Gandhi, Trevor Sweatman, Tiffany Seagroves},
TITLE = {Pivarubicin Is More Effective Than Doxorubicin Against  Triple-Negative Breast Cancer In Vivo},
JOURNAL = {Oncology Research},
VOLUME = {28},
YEAR = {2020},
NUMBER = {5},
PAGES = {451--465},
URL = {http://www.techscience.com/or/v28n5/48506},
ISSN = {1555-3906},
ABSTRACT = {Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the 
use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. 
Multidrug therapies achieve pathological cure rates of only 20–40%, a consequence of drug resistance and 
cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more 
effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the 
mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary 
TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X<sub>L</sub>, and Bcr-Abl. As a consequence, 
pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown 
in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was 
performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated 
with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by 
digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity 
was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors 
treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicletreated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of 
tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological 
analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence 
of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and 
more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin 
therapy is indicated.},
DOI = {10.3727/096504020X15898794315356}
}