New insights into the anticancer therapeutic potential of icaritin and its synthetic derivatives

Abstract

Icaritin is a natural prenylated flavonoid derived from the Chinese herb Epimedium. The compound has shown antitumor effects in various cancers, especially hepatocellular carcinoma (HCC). Icaritin exerts its anticancer activity by modulating multiple signaling pathways, such as IL‐6/JAK/STAT3, ER‐α36, and NF‐κB, affecting the tumor microenvironment and immune system. Several clinical trials have evaluated the safety and efficacy of icaritin in advanced HCC patients with poor prognoses, who are unsuitable for conventional therapies. The results have demonstrated that icaritin can improve survival, delay progression, and produce clinical benefits in these patients, with a favorable safety profile and minimal adverse events. Moreover, icaritin can enhance the antitumor immune response by regulating the function and phenotype of various immune cells, such as CD8+ T cells, MDSCs, neutrophils, and macrophages. These findings suggest that icaritin is a promising candidate for immunotherapy in HCC and other cancers. However, further studies are needed to elucidate the molecular mechanisms and optimal dosing regimens of icaritin and its potential synergistic effects with other agents. Therefore, this comprehensive review of the scientific literature aims to summarize advances in the knowledge of icaritin in preclinical and clinical studies as well as the pharmacokinetic, metabolism, toxicity, and mechanisms action to recognize the main challenge, gaps, and opportunities to develop a medication that cancer patients can use. Thus, our main objective was to clarify the current state of icaritin for use as an anticancer drug.

Hyaluronic acid-modified liposomes Potentiated in-vivo anti-hepatocellular carcinoma of icaritin

“…Icaritin exhibits a multifaceted mechanism of action against liver cancer, including inducing apoptosis through a caspase-dependent pathway, inhibiting cell proliferation by blocking the cell cycle and inducing cell cycle arrest, modulating various signaling pathways such as PI3K/AKT, MAPKs, and JAK/STATs, inhibiting tumor angiogenesis by suppressing VEGF and other angiogenic factors, enhancing the immune response by increasing cytokine production and activating immune cells, inhibiting the growth and self-renewal of cancer stem cells, and modulating the tumor microenvironment by suppressing pro-inflammatory cytokines and promoting immune cell infiltration ( Yang et al, 2019 ; Yin et al, 2020 ; Zhang et al, 2020 ; Lu et al, 2022 ; Reyes-Hernández et al, 2024 ). Despite its potential, the clinical application of icaritin for cancer treatment is currently limited by its low water solubility and restricted bioavailability.…”