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Review
. 2021 Dec 20;26(24):7696.
doi: 10.3390/molecules26247696.

Withaferin A: From Ancient Remedy to Potential Drug Candidate

Tahira Sultana  1 , Mohammad K Okla  2 , Madiha Ahmed  1   3 , Nosheen Akhtar  4 , Abdulrahman Al-Hashimi  2 , Hamada Abdelgawad  5 , Ihsan-Ul- Haq  1
Affiliations
Review

Withaferin A: From Ancient Remedy to Potential Drug Candidate

Tahira Sultana et al. Molecules. .

Abstract

Withaferin A (WA) is a pivotal withanolide that has conquered a conspicuous place in research, owning to its multidimensional biological properties. It is an abundant constituent in Withania somnifera Dunal. (Ashwagandha, WS) that is one of the prehistoric pivotal remedies in Ayurveda. This article reviews the literature about the pharmacological profile of WA with special emphasis on its anticancer aspect. We reviewed research publications concerning WA through four databases and provided a descriptive analysis of literature without statistical or qualitative analysis. WA has been found as an effective remedy with multifaceted mechanisms and a broad spectrum of pharmacological profiles. It has anticancer, anti-inflammatory, antiherpetic, antifibrotic, antiplatelet, profibrinolytic, immunosuppressive, antipigmentation, antileishmanial, and healing potentials. Evidence for wide pharmacological actions of WA has been established by both in vivo and in vitro studies. Further, the scientific literature accentuates the role of WA harboring a variable therapeutic spectrum for integrative cancer chemoprevention and cure. WA is a modern drug from traditional medicine that is necessary to be advanced to clinical trials for advocating its utility as a commercial drug.

Keywords: Withania somnifera; anticancer; antiherpes virus; antiinflammatory; antileishminial; antitumor; withaferin A.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of withaferin A.
Figure 2
Figure 2
Summarized and diagrammatic representation of mechanism of anticancer activity of Withaferin A. Withaferin A targets multiple cell proliferation and apoptosis pathways. Major apoptosis pathways include activation of Notch-4, Bax, FOXO3a, and extrinsic and intrinsic apoptosis pathways, p53 induction, p21cip1/waf1 activation, Hsp90/Cdc37 complex cleavage, ROS production, and microtubule cleavage. It also inhibits cancer proliferation by blocking Notch-1, Atk/JNK, PARP, STAT3 and inhibit metastasis by enhancing BRMS1 expression and decreasing expression of ANGPTL2, TNFSF12, IL6, ALDH-1, CD44, CD2, and extracellular matrix degrading protein ADAM8, PLAT, and UPA. It causes mitotic arrest by activating Cdk1, Cdc25C, Cdc25B, PCNA, and p34cdc2 protein and by inhibiting Adc20, MAD2, and KLF-4 proteins. Withaferin A also reduces NF-κB pathways, p-glycoprotein and expression of HPV oncoproteins thereby mediating p53 and pRb associated apoptosis. ↑ and ↓ indicates increase and decrease in expression level, respectively. Red and blue arrows (and) show pathways associated with cell proliferation and apoptosis respectively. Symbols formula image and formula image shows pathways stimulated and blocked respectively by WA.
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