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.
Graphical Abstract:

Keywords: Withaferin A, Withania somnifera, dietary supplement, anti-cancer activity, pharmacological mechanism, direct target


中文翻译：

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Withaferin A：一种膳食补充剂，具有作为癌症治疗抗肿瘤药物的潜力 - 药理学和机制

摘要：癌症作为全球头号死亡原因，严重威胁人类健康，开发有效的肿瘤治疗方法成为重大挑战。天然产物仍然是药物发现的重要资源。其中，睡茄素A (WA)是从著名膳食补充剂睡茄(Withania somnifera (L.) Dunal )中提取的最具活性的植物化合物，具有显着的抗肿瘤功效。在这篇手稿中，我们旨在全面总结WA作为潜在抗肿瘤候选药物的药理学特征，旨在为其进一步开发和前瞻性药物的发现做出贡献。通过对 PubMed、Science Direct 和 Web of Science 的文献进行广泛回顾，我们收集了大量证据，证明 WA 在体外和体内研究中对多种癌症具有显着的抗肿瘤作用。从机制上讲，WA通过诱导细胞周期停滞、细胞凋亡、自噬和铁死亡来发挥其抗肿瘤作用。此外，它还能抑制细胞增殖、癌症干细胞、肿瘤转移，并抑制上皮间质转化 (EMT) 和血管生成。多项研究已经确定了 WA 的直接靶蛋白，如波形蛋白、Hsp90、膜联蛋白 II 和 mFAM72A，而 BCR-ABL、Mortalin (mtHsp70)、Nrf2 和 c-MYB 是 WA 的潜在靶点。尽管其具有显着的抗肿瘤功效，但 WA 也存在一些局限性，包括潜在的毒性和口服生物利用度差，在将其视为抗肿瘤候选药物时需要解决这些问题。尽管如此，鉴于其具有前景的抗肿瘤特性，WA 仍然是未来药物开发的一个令人鼓舞的候选者。揭示WA作用的确切目标和综合机制是未来研究的一个重要方向。
图文摘要：

关键词：睡茄素 A、睡茄、膳食补充剂、抗癌活性、药理机制、直接靶点