Chetomin

Chetomin is a natural alkaloid derived from Chaetomium species, known for its significant anticancer and anti-inflammatory properties^[1]. Chetomin functions by inhibiting hypoxia-inducible factor-1 (HIF-1) and disrupting the interaction between HIF-1α and p300, thereby suppressing hypoxia-related gene transcription^[2]. Chetomin serves as an important tool compound for studying hypoxia signaling pathways^[3]. Additionally, Chetomin has demonstrated efficacy in tumor models by inhibiting tumor growth and angiogenesis^[4].

In vitro, Chetomin (1–100nM) treatment of non-small cell lung cancer (NSCLC) cell lines H1299 and H460 in tumor spheroid cultures for 2 weeks significantly inhibited spheroid formation and the expression of stemness markers (Sox2, Nanog, Oct4), reduced the proportion of cancer stem cells with high aldehyde dehydrogenase activity (ALDH⁺), and induced apoptosis via activation of caspase-3 and PARP cleavage. In non-stem NSCLC cells, Chetomin (1–10μM) treatment for 24 hours significantly inhibited cell proliferation and colony formation, induced cell cycle arrest in the sub-G0/G1 phase, and exerted cytotoxic effects through a caspase-3-dependent apoptotic mechanism^[5]. Chetomin (1.56–25nM) treatment of human multiple myeloma cell lines (HMCL) and primary myeloma cells for 4 days significantly inhibited cell growth and induced cytotoxicity, particularly in myeloma cells with high EP300/HIF-1α expression, while downregulating the expression of HIF-1α target genes (VEGF, IL-8, and CCL3)^[6].

In vivo, Chetomin (0.5mg/kg) was administered intraperitoneally to C57BL/6J mice exposed to LiCoO₂ (LCO) particles via oropharyngeal aspiration, with treatment starting one day before exposure and continuing for two days post-exposure. Chetomin significantly attenuated LCO-induced early lung inflammation, including neutrophil infiltration and elevated levels of IL-1β and IL-6, and effectively inhibited HIF-1α activation in lung tissue^[7]. Chetomin (1 and 5mg/kg) was administered via intraperitoneal injection to mice bearing U251-MG glioblastoma multiforme xenografts. Treatment was initiated when the tumor volume reached approximately 200mm³ and continued for 25 or 42 days. Chetomin significantly inhibited tumor growth in a dose-dependent manner and reduced the expression of p-FAK, p-AKT, and PCNA in tumor tissues^[8].

References:
[1] Staab A, Loeffler J, Said HM, et al. Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer. 2007 Nov 13;7:213.
[2] Bravo-Reyna C, Zentella A, Ventura-Gallegos J, et al. Experimental Lung Transplantation Related With HIF-1, VEGF, ROS. Assessment of HIF-1alpha, VEGF, and Reactive Oxygen Species After Competitive Blockade of Chetomin for Lung Transplantation in Rats. Physiol Res. 2024 Nov 19;73(5):809-817.
[3] Dewangan J, Srivastava S, Mishra S, et al. Chetomin induces apoptosis in human triple-negative breast cancer cells by promoting calcium overload and mitochondrial dysfunction. Biochem Biophys Res Commun. 2018 Jan 8;495(2):1915-1921.
[4] Yano K, Horinaka M, Yoshida T, et al. Chetomin induces degradation of XIAP and enhances TRAIL sensitivity in urogenital cancer cells. Int J Oncol. 2011 Feb;38(2):365-74.
[5] Min S, Wang X, Du Q, et al. Chetomin, a Hsp90/HIF1α pathway inhibitor, effectively targets lung cancer stem cells and non-stem cells. Cancer Biol Ther. 2020 Aug 2;21(8):698-708.
[6] Viziteu E, Grandmougin C, Goldschmidt H, et al. Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma. Br J Cancer. 2016 Mar 1;114(5):519-23.
[7] Sironval V, Palmai-Pallag M, Vanbever R, et al. HIF-1α is a key mediator of the lung inflammatory potential of lithium-ion battery particles. Part Fibre Toxicol. 2019 Sep 18;16(1):35.
[8] Lee J, Kim E, Chong K, et al. Atypical induction of HIF-1α expression by pericellular Notch1 signaling suffices for the malignancy of glioblastoma multiforme cells. Cell Mol Life Sci. 2022 Oct 2;79(10):537.

Chetomin是一种来源于Chaetomium属真菌的天然生物碱，具有显著的抗癌和抗炎作用^[1]。Chetomin通过抑制缺氧诱导因子-1（HIF-1）并阻断HIF-1α与p300的相互作用，抑制缺氧相关基因转录^[2]，是研究缺氧信号通路的重要工具化合物^[3]，此外Chetomin在肿瘤模型中表现出抑制肿瘤生长和血管生成的效果^[4]。

在体外，Chetomin（1–100nM）处理非小细胞肺癌（NSCLC）细胞系H1299和H460的肿瘤球体培养物2周，显著抑制了肿瘤球体的形成和干性标志物（Sox2、Nanog、Oct4）的表达，降低了具有高醛脱氢酶活性（ALDH⁺）的癌症干细胞亚群比例，并通过激活caspase-3和PARP剪切诱导细胞凋亡；而在非干性NSCLC细胞中，Chetomin（1–10μM）处理24小时显著抑制了细胞增殖和集落形成能力，诱导细胞周期阻滞于sub-G0/G1期，并通过caspase-3依赖的凋亡机制发挥细胞毒性作用^[5]。Chetomin（1.56–25nM）处理人多发性骨髓瘤细胞系（HMCL）和原代骨髓瘤细胞4天，显著抑制了细胞生长，诱导细胞毒性，尤其对EP300/HIF-1α高表达的骨髓瘤细胞敏感性更高，同时下调了HIF-1α靶基因（VEGF、IL-8和CCL3）的表达水平^[6]。

在体内，Chetomin（0.5mg/kg）通过腹腔注射给药，用于处理经口咽吸入LiCoO₂（LCO）颗粒的C57BL/6J小鼠模型，给药时间为颗粒暴露前1天及暴露后连续2天。Chetomin显著减少了LCO诱导的早期肺部炎症反应，包括中性粒细胞浸润、IL-1β和IL-6水平的升高，并有效抑制了肺组织中HIF-1α的激活^[7]。Chetomin（1和5mg/kg）通过腹腔注射给药，用于治疗U251-MG胶质母细胞瘤异种移植模型的小鼠，给药时间为肿瘤体积达到约200mm³时开始，持续25或42天。Chetomin以剂量依赖性方式显著抑制肿瘤生长，并减少肿瘤组织中p-FAK、p-AKT和PCNA的表达^[8]。