Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway

Xiu, Zhiru; Zhu, Yan; Li, Shanzhi; Yang, Xia; Li, Yue; Song, Gaojie; Jin, Ningyi; Fang, Jinbo; Han, Jicheng; Li, Yiquan; Li, Xiao

doi:10.1016/j.jff.2023.105441

Cited by 8 publications

(4 citation statements)

References 47 publications

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“…In addition, it was found that Betulinic acid, a terpene widely found in food, was also able to induce ferritin autophagy in HCC cells by modulating the NCOA4/FTH1 pathway, leading to the release of iron ions and causing cellular iron death. This was specifically demonstrated by the upregulation of NCOA4 and LC3 and the downregulation of FTH1 in ex vivo experiments (Xiu, Zhu, et al, 2023). Recently, Lv et al employed a metal–ligand synergistic enhancement (MLSE) strategy to fuse Betulin with iridium cyclopentadienyl (Ir‐Cp*) to form a complex to inhibit the ferritin autophagy pathway in cancer cells.…”

Section: Natural Products Regulate Hcc Through Autophagymentioning

confidence: 92%

“…Recent studies have shown that Esculetin, a coumarin analogue present in Rehmannia glutinosa var, inhibits the proliferation and migration of HUH7 and HCCLM3 cells in vitro and reduces the volume of HCC tissues in vivo. Mechanistically, it increases ferritin autophagy mainly by mediating the NCOA4 pathway, triggering the expression of NCOA4 and LC3 (Xiu, Li, et al, 2023). In addition, it was found that Betulinic acid, a terpene widely found in food, was also able to induce ferritin autophagy in HCC cells by modulating the NCOA4/FTH1 pathway, leading to the release of iron ions and causing cellular iron death.…”

Section: Natural Products Regulate Hcc Through Autophagymentioning

confidence: 99%

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Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives

Chen,

Tan,

Zhang

et al. 2024

Phytotherapy Research

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Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer‐related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy‐related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy‐modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/β‐catenin, Beclin‐1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double‐edged sword in HCC management.

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Section: Natural Products Regulate Hcc Through Autophagymentioning

confidence: 92%

Section: Natural Products Regulate Hcc Through Autophagymentioning

confidence: 99%

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives

Chen,

Tan,

Zhang

et al. 2024

Phytotherapy Research

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“…In addition, natural products such as vitamins, coumarins, and unsaturated fatty acids are considered potential ferroptosis inducers in cancer cells (Y. Vermonden et al, 2021;Xiu et al, 2023). Vitamin C increased intracellular iron levels by promoting ferritin degradation (X.…”

Section: Other Natural Productsmentioning

confidence: 99%

Ferroptosis: Potential opportunities for natural products in cancer therapy

Nie,

Shen,

Zhou

et al. 2023

Phytotherapy Research

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Cancer cells often exhibit defects in the execution of cell death, resulting in poor clinical outcomes for patients with many cancer types. Ferroptosis is a newly discovered form of programmed cell death characterized by intracellular iron overload and lipid peroxidation in the cell membrane. Increasing evidence suggests that ferroptosis is closely associated with a wide variety of physiological and pathological processes, particularly in cancer. Notably, various bioactive natural products have been shown to induce the initiation and execution of ferroptosis in cancer cells, thereby exerting anticancer effects. In this review, we summarize the core regulatory mechanisms of ferroptosis and the multifaceted roles of ferroptosis in cancer. Importantly, we focus on natural products that regulate ferroptosis in cancer cells, such as terpenoids, polyphenols, alkaloids, steroids, quinones, and polysaccharides. The clinical efficacy, adverse effects, and drug–drug interactions of these natural products need to be evaluated in further high‐quality studies to accelerate their application in cancer treatment.

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“…Natural products are one of the most promising components and precursors of anticancer drugs with various mechanisms of action and relatively low toxicity . Terpenes have been recognized as relevant secondary metabolites, − among which betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BetA) and related lupane-type pentacyclic triterpenoids have attracted a great interest in current drug discovery. − The ability of betulinic and betulonic acids to inhibit cancer cell growth was well established on different cell lines and primary cells from solid tumors. − …”

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confidence: 99%

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

Tsepaeva,

Salikhova,

Ishkaeva

et al. 2023

J. Nat. Prod.

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A convenient synthesis is presented for a new class of bioactive bifunctionalized conjugates of lupane-type triterpenoids with triphenylphosphonium (TPP) and glycopyranosyl targeting moieties. The main synthesis steps include glycosylation of haloalkyl esters of the triterpene acid at the C-3 position by the imidate derivatives of glycopyranose followed by the product modification at the C-28 position with triphenylphosphine. The conjugates of betulinic acid (BetA) with TPP and d-glucose, l-rhamnose, or d-mannose moieties were thus synthesized as potential next-generation BetA-derived anticancer compounds. LC-MS/MS analysis in glucose-free physiological solution indicated that the glycosides showed better accumulation in PC-3 prostate cancer cells than both BetA and TPP–BetA conjugate, while the transporting effect of monosaccharide residues increased as follows: d-mannose < l-rhamnose ≈ d-glucose. At saturated concentrations, the glycosides caused a disturbing effect on mitochondria with a more drastic drop in transmembrane potential but weaker overproduction of mitochondrial reactive oxygen species (ROS) compared to TPP–BetA conjugate. Cytotoxicity of the glycosides in culture medium was comparable with or higher than that of the nonglycosylated conjugate, depending on the cancer cell line, whereas the compounds were less active toward primary fibroblasts. Glycosylation tended to increase pro-apoptotic and decrease pro-autophagic activities of the BetA derivatives. Cytotoxicity of the synthesized glycosides was considered in comparison with the summarized data on the natural and modified BetA glycosides. The results obtained are important for the development of bifunctionalized conjugates of triterpenoids with an increased cancer cell targetability.

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Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway

Cited by 8 publications

References 47 publications

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives

Ferroptosis: Potential opportunities for natural products in cancer therapy

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

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