Clitocine
(Synonyms: 克力托辛) 目录号 : GC60111
Clitocine是一种腺苷核苷类似物，是一种有效的通透剂(readthrough)。Clitocine可诱导携带p53无义突变等位基因的细胞产生p53蛋白。Clitocine可通过靶向Mcl-1诱导多药耐药肿瘤细胞凋亡。具有抗癌活性。
Cas No.:105798-74-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Clitocine, an adenosine nucleoside analog, is a potent and efficacious readthrough agent. Clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. Clitocine can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. Anticancer activity[1][2].
Clitocine (0-0.8μM; 24 hours) enhances TRAIL-lethality in in LS411N and SW620 cells. Clitocine (0.2μM; 36 hours) significantly potentiates TRAIL-mediated apoptosis[2].
Citocine (0.3-3 mg/kg; s.c.; five times per week)-induced p53 inhibits CAOV-33p53-UAA136 tumor growth in a xenograft model[1]. Animal Model: nu/nu mice (CAOV-3p53-UAA136 xenograft tumors)[1]
[1]. Friesen WJ, et al. The nucleoside analog clitocine is a potent and efficacious readthrough agent. RNA. 2017;23(4):567-577. [2]. Sun JG, et al. Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation. Apoptosis. 2016;21(10):1144-1157.
| Cas No. | 105798-74-1 | SDF | |
| 别名 | 克力托辛 | ||
| Canonical SMILES | O[C@H]1[C@H](NC2=NC=NC(N)=C2[N+]([O-])=O)O[C@H](CO)[C@H]1O | ||
| 分子式 | C9H13N5O6 | 分子量 | 287.23 |
| 溶解度 | 储存条件 | ||
| 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 | 3.4815 mL | 17.4077 mL | 34.8153 mL |
| 5 mM | 0.6963 mL | 3.4815 mL | 6.9631 mL |
| 10 mM | 0.3482 mL | 1.7408 mL | 3.4815 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。
Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation
Apoptosis 2016 Oct;21(10):1144-57.PMID:27421828DOI:10.1007/s10495-016-1273-y.
Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with Clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of Clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by Clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate Clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, Clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by Clitocine. In fact, more ubiquitinated Mcl-1 was detected under Clitocine treatment. Our findings indicate that Clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.
The nucleoside analog Clitocine is a potent and efficacious readthrough agent
RNA 2017 Apr;23(4):567-577.PMID:28096517DOI:10.1261/rna.060236.116.
Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog Clitocine as a potent and efficacious suppressor of nonsense mutations. We determined that incorporation of Clitocine into RNA during transcription is a prerequisite for its readthrough activity; the presence of Clitocine in the third position of a premature stop codon directly induces readthrough. We demonstrate that Clitocine can induce the production of p53 protein in cells harboring p53 nonsense-mutated alleles. In these cells, Clitocine restored production of full-length and functional p53 as evidenced by induced transcriptional activation of downstream p53 target genes, progression of cells into apoptosis, and impeded growth of nonsense-containing human ovarian cancer tumors in xenograft tumor models. Thus, Clitocine induces readthrough of nonsense mutations by a previously undescribed mechanism and represents a novel therapeutic modality to treat cancers and genetic diseases caused by nonsense mutations.
Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo
Apoptosis 2014 May;19(5):871-82.PMID:24563182DOI:10.1007/s10495-014-0969-0.
Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that Clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that Clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after Clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, Clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that Clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.
Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak
Cancer Lett 2014 Dec 28;355(2):253-63.PMID:25304383DOI:10.1016/j.canlet.2014.09.024.
ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT-737. At the present study, we observed that Clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, Clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which Clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that Clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of Clitocine and ABT-737. Finally, Clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest Clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis.
Clitocine reversal of P-glycoprotein associated multi-drug resistance through down-regulation of transcription factor NF-κB in R-HepG2 cell line
PLoS One 2012;7(8):e40720.PMID:22927901DOI:10.1371/journal.pone.0040720.
Multidrug resistance (MDR) is one of the major reasons for failure in cancer chemotherapy and its suppression may increase the efficacy of therapy. The human multidrug resistance 1 (MDR1) gene encodes the plasma membrane P-glycoprotein (P-gp) that pumps various anti-cancer agents out of the cancer cell. R-HepG2 and MES-SA/Dx5 cells are doxorubicin induced P-gp over-expressed MDR sublines of human hepatocellular carcinoma HepG2 cells and human uterine carcinoma MES-SA cells respectively. Herein, we observed that Clitocine, a natural compound extracted from Leucopaxillus giganteus, presented similar cytotoxicity in multidrug resistant cell lines compared with their parental cell lines and significantly suppressed the expression of P-gp in R-HepG2 and MES-SA/Dx5 cells. Further study showed that the Clitocine increased the sensitivity and intracellular accumulation of doxorubicin in R-HepG2 cells accompanying down-regulated MDR1 mRNA level and promoter activity, indicating the reversal effect of MDR by Clitocine. A 5'-serial truncation analysis of the MDR1 promoter defined a region from position -450 to -193 to be critical for Clitocine suppression of MDR1. Mutation of a consensus NF-κB binding site in the defined region and overexpression of NF-κB p65 could offset the suppression effect of Clitocine on MDR1 promoter. By immunohistochemistry, Clitocine was confirmed to suppress the protein levels of both P-gp and NF-κB p65 in R-HepG2 cells and tumors. Clitocine also inhibited the expression of NF-κB p65 in MES-SA/Dx5. More importantly, Clitocine could suppress the NF-κB activation even in presence of doxorubicin. Taken together; our results suggested that Clitocine could reverse P-gp associated MDR via down-regulation of NF-κB.