Lucanthone
(Synonyms: 硫蒽酮) 目录号 : GC33126
Lucanthone is a novel autophagic inhibitor and also an orally available thioxanthone-based DNA intercalator and inhibitor of the DNA repair enzyme apurinic-apyrimidinic endonuclease 1.
Cas No.:479-50-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Cell viability is assessed by MTT assay. Cells are seeded into 96-well microculture plates at 10,000 cells per well and allowed to attach for 24 h. Cells are then treated with Lucanthone (0, 0.5, 1, 5, 10, 20 and 40 μM), Chloroquine, Vorinostat, or combinations for 72 h. Following drug treatment, MTT is added and cell viability is quantified using a BioTek microplate reader. Effects on cell viability are also determined by measuring ATP levels using the ATPlite assay system and by trypan blue exclusion. Pro-apoptotic effects following in vitro drug exposure are quantified by propidium iodide (PI) staining and fluorescence-activated cell sorting (FACS) analysis of sub-G0/G1 DNA content[2]. |
References: [1]. Chowdhury SM, et al. Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme. Nanomedicine. 2015 Jan;11(1):109-18. | |
Lucanthone is a novel autophagic inhibitor and also an orally available thioxanthone-based DNA intercalator and inhibitor of the DNA repair enzyme apurinic-apyrimidinic endonuclease 1.
| Cas No. | 479-50-5 | SDF | |
| 别名 | 硫蒽酮 | ||
| Canonical SMILES | O=C1C2=C(SC3=C1C=CC=C3)C(C)=CC=C2NCCN(CC)CC | ||
| 分子式 | C20H24N2OS | 分子量 | 340.48 |
| 溶解度 | DMSO : 25 mg/mL (73.43 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.937 mL | 14.6852 mL | 29.3703 mL |
| 5 mM | 0.5874 mL | 2.937 mL | 5.8741 mL |
| 10 mM | 0.2937 mL | 1.4685 mL | 2.937 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Lucanthone, Autophagy Inhibitor, Enhances the Apoptotic Effects of TRAIL through miR-216a-5p-Mediated DR5 Upregulation and DUB3-Mediated Mcl-1 Downregulation
Int J Mol Sci 2021 Dec 21;23(1):17.PMID:35008442DOI:10.3390/ijms23010017.
A Lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether Lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with Lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of DUB3 markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with Lucanthone and TRAIL-induced apoptosis. Moreover, Lucanthone increased expression level of DR5 mRNA via downregulation of miR-216a-5p. Transfection of miR-216a-5p mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that Lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of miR-216a-5p and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells.
Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo
Front Oncol 2022 Apr 14;12:852940.PMID:35494072DOI:10.3389/fonc.2022.852940.
Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage Lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that Lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo Lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that Lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.
Lucanthone and its derivative hycanthone inhibit apurinic endonuclease-1 (APE1) by direct protein binding
PLoS One 2011;6(9):e23679.PMID:21935361DOI:10.1371/journal.pone.0023679.
Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC(50) values for inhibition of APE1 incision of depurinated plasmid DNA by Lucanthone and hycanthone were 5 µM and 80 nM, respectively. The K(D) values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for Lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of Lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by Lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of Lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by Lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage.
Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis
J Biol Chem 2011 Feb 25;286(8):6602-13.PMID:21148553DOI:10.1074/jbc.M110.151324.
Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This pathway enables cancer cells to undergo self-digestion to generate ATP and other essential biosynthetic molecules to temporarily avoid cell death. Therefore, disruption of autophagy may sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis. Chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors. Because both of these agents induce ocular toxicity, novel inhibitors of autophagy with a better therapeutic index are needed. Here we demonstrate that the small molecule Lucanthone inhibits autophagy, induces lysosomal membrane permeabilization, and possesses significantly more potent activity in breast cancer models compared with chloroquine. Exposure to Lucanthone resulted in processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes, but impaired autophagic degradation as revealed by transmission electron microscopy and the accumulation of p62/SQSTM1. Microarray analysis, qRT-PCR, and immunoblotting determined that Lucanthone stimulated a large induction in cathepsin D, which correlated with cell death. Accordingly, knockdown of cathepsin D reduced lucanthone-mediated apoptosis. Subsequent studies using p53(+/+) and p53(-/-) HCT116 cells established that Lucanthone induced cathepsin D expression and reduced cancer cell viability independently of p53 status. In addition, Lucanthone enhanced the anticancer activity of the histone deacetylase inhibitor vorinostat. Collectively, our results demonstrate that Lucanthone is a novel autophagic inhibitor that induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models.
Autophagy: a multifaceted player in the fate of sperm
Hum Reprod Update 2022 Feb 28;28(2):200-231.PMID:34967891DOI:10.1093/humupd/dmab043.
Background: Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear. Objective and rationale: We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility. Search methods: In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'Lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines. Outcomes: (i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization. Wider implications: Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.