Ashwagandha is also recommended as a tonic for overall well-being ( 13) and the extract of Withania somnifera L.
Withaferin A (WA) is a bioactive compound derived from the medicinal plant Withania somnifera (commonly known as ashwagandha or Indian winter cherry), which has been safely used for centuries in the Indian Ayurvedic medicine practice for the treatment of various ailments ( 8– 13). Natural products have received increasing attention in recent years for the discovery of novel cancer preventive and therapeutic agents ( 7). Therefore, novel agents for prevention and treatment of human breast cancers, especially hormone-independent breast cancers, are highly desirable. Moreover, selective ER modulators have serious side effects including increased risk of uterine cancer, thromboembolism, cataracts, and perimenopausal symptoms ( 5, 6). Although selective estrogen receptor (ER) modulators (e.g., tamoxifen) seem promising for prevention of breast cancer, this strategy is largely ineffective against ER-negative breast cancers ( 5, 6). Because some of these risk factors are not easily modifiable (e.g., genetic predisposition), other strategies for reduction of the breast cancer risk must be considered. The known risk factors for breast cancer include family history, Li-Fraumeni syndrome, atypical hyperplasia of the breast, late age at first full-term pregnancy, early menarche, and late menopause ( 2– 4). īreast cancer continues to be a leading cause of cancer-related deaths in women worldwide despite significant advances in screening techniques leading to early detection of the disease ( 1). These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice.
The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The cytoplasmic histone–associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells.
The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone–associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner.
We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments.