ABSTRACT
Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Benzophenanthridines/therapeutic use , Breast Neoplasms/drug therapy , Folic Acid Antagonists/therapeutic use , Isoquinolines/therapeutic use , Neoplasm Proteins/antagonists & inhibitors , Neoplasms, Basal Cell/drug therapy , Tetrahydrofolate Dehydrogenase/metabolism , Animals , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Benzophenanthridines/adverse effects , Benzophenanthridines/pharmacology , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm , Female , Folic Acid Antagonists/adverse effects , Folic Acid Antagonists/pharmacology , Humans , Isoquinolines/adverse effects , Isoquinolines/pharmacology , Methotrexate/pharmacology , Mice , Mice, Inbred Strains , Necrosis , Neoplasm Proteins/metabolism , Neoplasm Transplantation , Neoplasms, Basal Cell/enzymology , Neoplasms, Basal Cell/pathology , Random Allocation , Tetrahydrofolate Dehydrogenase/chemistry , Tumor Burden/drug effectsABSTRACT
Many cell kinases exert their proliferative and pro-survival effects through activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Basal-like breast cancer is a subtype that can be identified by molecular analysis and often includes tumors lacking expression of estrogen receptor/progesterone receptor or human epidermal growth factor receptor, also known as triple-negative breast cancers. Triple-negative cancers comprise < 20% of all breast cancers and have no obvious mechanism driving proliferation, yet these tumors demonstrate higher levels of Akt activation compared with non-triple-negative breast cancers. This suggests a possible role for targeting the PI3K pathway for the treatment of this subset of aggressive cancers. Most clinical trials which have attempted targeting the PI3K/Akt pathway in triple-negative breast cancer have involved the use of EGFR inhibitors with limited success. Novel agents targeting PI3K are under development in early-phase clinical trials and may demonstrate benefit in combination with chemotherapy or other targeted agents such as mitogen-activated protein kinase inhibitors for the treatment of triple-negative or basal-like breast cancer.
