Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Abstract

Cancer, as the leading cause of death worldwide, poses a serious threat to human health, making the development of effective tumor treatments a significant challenge. Natural products continue to serve as crucial resources for drug discovery. Among them, Withaferin A (WA), the most active phytocompound extracted from the renowned dietary supplement Withania somnifera (L.) Dunal, exhibits remarkable anti-tumor efficacy. In this manuscript, we aim to comprehensively summarize the pharmacological characteristics of WA as a potential anti-tumor drug candidate, with the objective of contributing to its further development and the discovery of prospective drugs. Through an extensive review of literature from PubMed, Science Direct, and Web of Science, we have gathered substantial evidence showcasing WA’s significant anti-tumor effects against a wide range of cancers in both in vitro and in vivo studies. Mechanistically, WA exerts its anti-tumor influence by inducing cell cycle arrest, apoptosis, autophagy, and ferroptosis. Additionally, it inhibits cell proliferation, cancer stem cells, tumor metastasis, and also suppresses epithelial-mesenchymal transition (EMT) and angiogenesis. Several studies have identified direct target proteins of WA, such as vimentin, Hsp90, annexin II and mFAM72A, while BCR-ABL, Mortalin (mtHsp70), Nrf2, and c-MYB are potential targets of WA. Notwithstanding its remarkable anti-tumor efficacy, there are some limitations associated with WA, including potential toxicity and poor oral bioavailability, which need to be addressed when considering it as an anti-tumor candidate agent. Nevertheless, I given its promising anti-tumor attributes, WA remains an encouraging candidate for future drug development. Unveiling the exact target and comprehensive mechanism of WA’s action represents a crucial research direction to pursue in the future.

Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies

“…The significant reduction in tumor size and postponement of tumor growth was observed in comparison to the control group. Furthermore, at therapeutic levels, WFA has a favorable safety profile, with few reported side effects [196].…”

Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?

“…One of its remarkable properties is its anti-cancer activity, which has been extensively studied both in vitro and in vivo. Withaferin A has been found to interact with key molecules involved in carcinogenesis, leading to its pro-apoptotic effect [ 181 ].…”

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

“…Withaferin A (WA) is a natural product isolated from withania that targets vimentin and has anti-inflammatory and anti-tumor properties. 207 By inducing ferroptosis, WA inhibited cell viability, invasive ability, vasculogenic mimicry (VM) formation, and VE-cadherin promoter levels in HepG2 and SNU449 cells, thereby attenuating hepatocellular carcinoma metastatic potential and sorafenib resistance. 126 WA has now been found to have multiple pathways for inducing ferroptosis.…”