Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives

Abstract

Withaferin A (WA), a manifold studied, C28-steroidal lactone withanolide found in Withania somnifera. Given its unique beneficial effects, it has gathered attention in the era of modern science. Cancer, being considered a "hopeless case and the leading cause of death worldwide, and the available conventional therapies have many lacunae in the form of side effects. The poly pharmaceutical natural compound, WA treatment, displayed attenuation of various cancer hallmarks by altering oxidative stress, promoting apoptosis, and autophagy, inhibiting cell proliferation, reducing angiogenesis, and metastasis progression. The cellular proteins associated with antitumor pathways were also discussed. WA structural modifications attack multiple signal transduction pathways and enhance the therapeutic outcomes in various diseases. Moreover, it has shown validated pharmacological effects against multiple neurodegenerative diseases by inhibiting acetylcholesterinases and butyrylcholinesterases enzyme activity, antidiabetic activity by upregulating adiponectin and preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ), cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis. The current review is an extensive survey of various WA associated disease targets, its pharmacokinetics, synergistic combination, modifications, and biological activities.

Keywords: Withaferin A; anticancer; autophagy; chaperone.

Figure 1

Structure of Withaferin A.

Figure 2

Metabolites of Withaferin A (a) 2,3-dihydro-3β-methoxy Withaferin A; (b) 2,3-Dihydrowithaferin A-3β-O-sulphate; (c,d) cysteine and glutathione conjugates of Withaferin A.

Figure 3

Withaferin A associated anticancer protein targets.