Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal

Abstract

Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.

Keywords: angiogenesis; apoptosis; cancer; chemoresistance; formulations; withaferin A.

Figure 1

Chemical structure of withaferin A.

Figure 2

Mechanism of action of withaferin A against cancer cells: Withaferin A caused dysfunction of mitochondria and disruption of mitotic spindle assembly of cancer cells by producing excessive ROS that can lead to apoptosis. Withaferin A can also inhibit the activities of β catenin and β tubulin and can disrupt the actin cytoskeleton. Activation of p53 function through withaferin A leads to apoptosis in cancer cells. Withaferin A also increased the rate of apoptosis in cancer cells by reducing the levels of antiapoptotic genes/proteins, such as Bcl-2 and B-Bcl-xL. Abbreviations: Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma-extra-large; ROS, reactive oxygen species.

Figure 3

Withaferin A intercedes in anti-inflammatory function in tumor cells via TNF-α, IL-1, and IL-7. Abbreviations: IL-1, interleukin-1; IL-7, interleukin-7; and TNF-α, tumor necrosis factor-α.

Figure 4

The combined treatment of doxorubicin (DOX) and withaferin A on cancer cells. It can lead to enhanced ROS production, destruction of DNA, initiation of autophagy, and increased expression of LC3B autophagy marker as well as cleavage of caspase-3.

Figure 5

Antiangiogenic and antimetastatic properties of withaferin A. Abbreviations: CSCs, cancer stem cells; CXCR4, C-X-C chemokine receptor type 4; MMP2; matrix metalloproteinases; Pyk2, proline-rich tyrosine kinase 2; ROCK2, Rho-associated coiled-coil-containing protein kinase 2; TGF-β, transforming growth factor-β; and VEGF, vascular endothelial growth factor.