Evaluating anticancer properties of Withaferin A-a potent phytochemical

Abstract

Withaferin A is a C28 steroidal lactone derived from the plant Withania somnifera, commonly known as Ashwagandha. Withaferin A has received great attention for its anticancer properties noted in cancer cells of various origins. Extracts of Withania somnifera have been used in traditional Ayurvedic and Unani Indian medicine for their various pharmacological benefits. In recent years, Withania somnifera or Ashwagandha extract has become popularized as a health supplement marketed for its stress and anxiety reducing effects. Withaferin A is one of the most studied withanolides extracted from Withania somnifera that has gained great attention for its anticancer, anti-inflammatory, metabolic, and pro-apoptotic effects. Extensive in vivo and in vitro studies have depicted Withaferin A's interactions with key role players in cancerous activity of the cell to exert its pro-apoptotic effects. Withaferin A interactions with NF-κB, STAT, Hsp90, ER-α, p53, and TGF-β have noted inhibition in cancer cell proliferation and cell cycle arrest in G2/M stage, ultimately leading to apoptosis or cell death. This review highlights pro-apoptotic properties of Withaferin A including generation of reactive oxidative species, Par-4 activation, endoplasmic reticulum stress (ER) induction, and p53 activation. Analysis of Withaferin A's involvement in various oncogenic pathways leading to malignant neoplasm and its pharmacologic activity in conjunction with various cancer drugs provides promising evidence in therapeutic potential of Withaferin A as a cancer treatment.

Keywords: Ashwagandha; Withaferin A; Withania somnifera; apoptosis; cancer; cancer treatment; withanolides.

FIGURE 1

Structure of Withaferin A. Withaferin A is a C28 steroidal lactone with substituents important for biological activity. Notable substituents include a 5β,6β epoxide ring, a lactone side chain, and an α,β-unsaturated ketone.

FIGURE 2

Apoptotic activity of Withaferin A. Withaferin A’s apoptotic activity can occur through various interactions with intercellular components/proteins. These include activation of Par-4 to increase its expression, activation of p53, endoplasmic reticulum (ER) stress induction, cell cycle arrest, and interaction with mitochondria to generate reactive oxidative species (ROS).

FIGURE 3

Withaferin A interactions. Withaferin A interactions with multiple intracellular proteins leads to modulation of cancerous activity of cell. Withaferin A has antagonistic activity with NOTCH-1, VEGFR, and JAK/STAT in cytoplasm. In cell’s nucleus, Withaferin A inhibits activity of transcription factors NF-κB, ER-α, and STAT3; preventing transcription of their downstream products. These interactions inhibit cancerous cell activity marked by cell proliferation, epithelial to mesenchymal transition, angiogenesis, cell proliferation, metastasis, and cell invasion.