Open Access
ARTICLE
Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo
Leonard Lothstein*, Judith Soberman†, Deanna Parke*, Jatin Gandhi*, Trevor Sweatman‡, Tiffany Seagroves*
* Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
† Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
‡ Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN, USA
Oncology Research 2020, 28(5), 451-465. https://doi.org/10.3727/096504020X15898794315356
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
L, 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.
Keywords
Cite This Article
Lothstein, L., Soberman, J., Parke, D., Gandhi, J., Sweatman, T. et al. (2020). Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo.
Oncology Research, 28(5), 451–465.