Staurosporine(CGP 41251)
(Synonyms: 星形孢菌素; Antibiotic AM-2282; STS; AM-2282) 目录号 : GC15299
A potent inhibitor of protein kinase C
Cas No.:62996-74-1
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
THP-1 cells |
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Preparation Method |
THP-1 cells were plated at 4 × 106 cells per ml in 6- or 24-well plates for performing the caspase 3 fluorometric assay or in 8-well chamber slides for the TUNEL assay.Live or dead microsporidia spores were added to wells at a parasite to host cell ratio of 3:1. Apoptosis was experimentally induced by treatment with 1 uM of staurosporine after 4 h. |
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Reaction Conditions |
1 uM; 4h |
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Applications |
Macrophages incubated with live E. cuniculi and induced by staurosporine exhibited significantly fewer TUNEL-positive cells compared to macrophages incubated without microsporidia and induced with staurosporine. |
| Animal experiment [2]: | |
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Animal models |
female immunocompromised mice, Nu/J-Foxn1 nu/nu |
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Preparation Method |
When tumors reached a volume of - 65 mm3, mice were randomized into one of four treatment groups: placebo, staurosporine, lapatinib, or combined staurosporine and lapatinib. For the staurosporine single and combination treatment groups, mice received 3 mg/kg staurosporine via oral gavage twice a week. For the lapatinib single and combination treatment groups, mice received 50 mg/kg lapatinib via oral gavage twice a week. Tumor measurements were taken twice weekly on the days of treatment./p> |
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Dosage form |
3 mg/kg; p.o. |
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Applications |
Staurosporine by itself showed no effects on tumor growth, likely due to the fact that we used a low dose of staurosporine (3 mg/kg). However, the combination of 3 mg/kg staurosporine and 50 mg/kg lapatinib impaired tumor growth in a statistically significant manner. |
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References: [1].Sokolova YY, et al. Encephalitozoon cuniculi and Vittaforma corneae (Phylum Microsporidia) inhibit staurosporine-induced apoptosis in human THP-1 macrophages in vitro. Parasitology. 2019 Apr;146(5):569-579. [2].Zambrano JN, et al. Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase. Oncotarget. 2018 Nov 13;9(89):35962-35973. |
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Staurosporin, a small kinase inhibitor, is an alkaloid derived from the bacterium Streptomyces staurosporeus.[1] Staurosporine can block the ATP-binding site of the enzimes and induce apoptosis by activation of caspase-3 in higher eukaryotes.[2]
In vitro experiment it shown that treatment with 50 nM of Staurosporin, there is a single-cell migration of breast carcinoma cells on plastic, fibronectin, or laminin surfaces.[1] Staurosporine killed Acanthamoeba trophozoites in a dose dependent way with IC50 and IC90 values of 0.265?±?0.057 and 1.27?±?0,007?μg/mL, respectively.[2] In vitro, treatment with a low concentration (10(-7) M) of staurosporine in cultured rat astrocytes, there is a significantly increased proportion of early apoptotic cells after regeneration in a staurosporine free medium. However, treatment with a higher (10(-6) M) concentration of staurosporine, there is further obviously increased necroptosis after regeneration in a staurosporine free medium.[3] In vitro efficacy test it indicated that 1 μM STS was able to activate the autophagy pathway in SH-SY5Y cells.[4] In addition, treatment with 5 to 50 μM of staurosporine, conidial cell viability decreased in a concentration-dependent manner, suggesting that staurosporine has potent antifungal activity against N. crassa conidia.[5]
In vivo efficacy study it demonstrated that mice were treated with 3 mg/kg staurosporine via oral gavage twice a week has no effects on tumor growth. But mice were treated with the combination of 3 mg/kg staurosporine and 50 mg/kg lapatinib inhibited the tumor growth obviously.[6]
References:
[1].Meyer FAH, et al. The Presence of Yin-Yang Effects in the Migration Pattern of Staurosporine-Treated Single versus Collective Breast Carcinoma Cells. Int J Mol Sci. 2021 Nov 4;22(21):11961.
[2].Cartuche L, et al. Staurosporine from Streptomyces sanyensis activates Programmed Cell Death in Acanthamoeba via the mitochondrial pathway and presents low in vitro cytotoxicity levels in a macrophage cell line. Sci Rep. 2019 Aug 12;9(1):11651.
[3].?imenc J, et al. Staurosporine induces apoptosis and necroptosis in cultured rat astrocytes. Drug Chem Toxicol. 2012 Oct;35(4):399-405.
[4].Brunelli F, et al. PINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage. Cells. 2022 Feb 15;11(4):678.
[5].Castro A, et al. Rotenone enhances the antifungal properties of staurosporine. Eukaryot Cell. 2010 Jun;9(6):906-14.
[6].Zambrano JN, et al. Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase. Oncotarget. 2018 Nov 13;9(89):35962-35973.
Staurosporin 是一种小激酶抑制剂，是一种从细菌 Streptomyces staurosporeus 中提取的生物碱。[1] Staurosporine 可以阻断酶的 ATP 结合位点，并通过激活 caspase-3 诱导细胞凋亡在高等真核生物中。[2]
体外实验表明，50 nM Staurosporin 处理后，乳腺癌细胞在塑料、纤连蛋白或层粘连蛋白表面出现单细胞迁移。[1] Staurosporine 杀死棘阿米巴滋养体呈剂量依赖性，IC50 和 IC90 值分别为 0.265 ± 0.057 和 1.27 ± 0,007 μg/mL。[2] 在体外，用低浓度 (10(-7) M) 处理在培养的大鼠星形胶质细胞中，星形胶质细胞在不含星形胶质细胞的培养基中再生后，早期凋亡细胞的比例显着增加。然而，用更高（10(-6) M）浓度的星形孢菌素处理，在无星形孢菌素培养基中再生后坏死性凋亡进一步明显增加。[3]体外药效试验表明，1 μM STS 能够激活 SH-SY5Y 细胞的自噬途径。[4] 此外，用 5 至 50 μM 星形孢菌素处理后，分生孢子细胞活力呈浓度依赖性下降，表明星形孢菌素对 N. crassa 分生孢子具有有效的抗真菌活性。[5]
体内功效研究表明，每周两次通过口服强饲法以 3 mg/kg 星形孢菌素处理小鼠对肿瘤生长没有影响。但小鼠用 3 mg/kg 星形孢菌素和 50 mg/kg 拉帕替尼联合治疗可明显抑制肿瘤生长。[6]
| Cas No. | 62996-74-1 | SDF | |
| 别名 | 星形孢菌素; Antibiotic AM-2282; STS; AM-2282 | ||
| 化学名 | (5S,6R,7R,9R)-6-methoxy-5-methyl-7-(methylamino)-6,7,8,9,15,16-hexahydro-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b,h]cyclonona[jkl]cyclopenta[e]-as-indacen-14(5H)-one | ||
| Canonical SMILES | O=C(NC1)C2=C1C3=C(C4=C2C5=C(C=CC=C5)N4[C@H]6C[C@@H](NC)[C@@H](OC)[C@]7(C)O6)N7C8=CC=CC=C83 | ||
| 分子式 | C28H26N4O3 | 分子量 | 466.53 |
| 溶解度 | ≥ 11.6mg/mL in DMSO | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1435 mL | 10.7174 mL | 21.4348 mL |
| 5 mM | 0.4287 mL | 2.1435 mL | 4.287 mL |
| 10 mM | 0.2143 mL | 1.0717 mL | 2.1435 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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2.
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Acute myeloid leukaemia
For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm
Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i's in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i's remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation
Background: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.
Methods: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.
Results: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.
Conclusions: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
Acute myeloid leukemia: 2021 update on risk-stratification and management
Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely benefit from treatment. Based on randomized trials CPX 351, midostaurin, gemtuzumab ozogamicin, and venetoclax, the latter three when combined with other drugs, should now be considered standard therapy. Knowledge of the likely results with these therapies is essential in deciding whether to recommend them or participate in a clinical trial, possibly including these drugs. Hence here, in the context of established prognostic algorithms, we review results with the recently- approved drugs compared with their predecessors and describe other potential options. We discuss benefit/risk ratios underlying the decision to offer allogeneic transplant and emphasize the importance of measurable residual disease. When first seeing a newly-diagnosed patient physicians must decide whether to offer conventional treatment or investigational therapy, the latter preferably in the context of a clinical trial. As noted below, such trials have led to changes in what today is considered "conventional" therapy compared to even 1-2 years ago. In older patients decision making has often included inquiring whether specific anti-AML therapy should be offered at all, rather than focusing on a purely palliative approach emphasizing transfusion and antibiotic support, with involvement of a palliative care specialist.
How I treat acute myeloid leukemia in the era of new drugs
The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.