Gamitrinib TPP
目录号 : GC33030
Gamitrinib TPP是一种Gamitrinib（GA）线粒体基质抑制剂。Gamitrinib TPP是一种线粒体靶向HSP90抑制剂，具有抗癌活性，用于化学干扰线粒体蛋白质折叠并诱导线粒体自噬诱导。
Cas No.:1131626-46-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
Cell lines | HeLa cells |
Preparation Method | HeLa cells stably expressing EGFP-Parkin were seeded in optical plates, treated with 10μM Gamitrinib TPP for 4h or 8h. The effect of Gamitrinib TPP on Parkin translocation was analyzed using high-content imaging (HCI). |
Reaction Conditions | 10μM; 4h or 8h |
Applications | Gamitrinib TPP treatment robustly induced Parkin translocation over time. |
| Animal experiment [2]: | |
Animal models | Nu/Nu mice |
Preparation Method | Nu/Nu mice were implanted subcutaneously with 1×106 LN229 glioblastoma cells. After tumor formation, groups were formed. Mice were treated intraperitoneally with vehicle, OTX015 (50mg/kg), Gamitrinib TPP (5mg/kg) or both agents (5 days on, 2 days off in week 1 and 2; 3 times a week in week 3 for 3 weeks). Tumor growth curves show the development of tumor size for each treatment group. |
Dosage form | 5mg/kg, 5 days on, 2 days off in week 1 and 2; 3 times a week in week 3 for 3 weeks; i.p. |
Applications | Gamitrinib-TPP and OTX015 monotherapy only partially inhibited tumor growth, while combination treatment with Gamitrinib-TPP and OTX015 significantly inhibited tumor growth and caused tumor regression. |
References: | |
Gamitrinib TPP is a Gamitrinib (GA) mitochondrial matrix inhibitor[1]. Gamitrinib TPP is a mitochondrial-targeted HSP90 inhibitor with anticancer activity used to chemically interfere with mitochondrial protein folding and induce mitophagy[2, 3].
In vitro, Gamitrinib TPP (10μM) treatment of HeLa cells stably expressing EGFP-Parkin for 4h and 8h induced Parkin (an E3 ubiquitin ligase) translocation in a time-dependent manner, induced mitophagy, and increased NP40 and SDS-insoluble proteins in mitochondria[4]. Gamitrinib TPP (15-20μM) treatment of glioblastoma cell lines (LN229, U251, U87 cells) for 16h concentration-dependently inhibited cell viability and induced mitochondrial apoptosis and autophagy[5].
In vivo, Gamitrinib TPP (5mg/kg) treated with intraperitoneal injection for 3 weeks in mice bearing a human glioma xenograft model partially inhibited tumor growth, and combined treatment with OTX015 significantly inhibited tumor growth and caused tumor regression[6].
References:
[1] Kang B H, Siegelin M D, Plescia J, et al. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer[J]. Clinical Cancer Research, 2010, 16(19): 4779-4788.
[2] Wei S, Yin D, Yu S, et al. Antitumor activity of a mitochondrial-targeted HSP90 inhibitor in gliomas[J]. Clinical Cancer Research, 2022, 28(10): 2180-2195.
[3] Hayat U, Elliott G T, Olszanski A J, et al. Feasibility and safety of targeting mitochondria for cancer therapy–preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor[J]. Cancer biology & therapy, 2022, 23(1): 117-126.
[4] Fiesel F C, James E D, Hudec R, et al. Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy[J]. Oncotarget, 2017, 8(63): 106233.
[5] Siegelin M D, Dohi T, Raskett C M, et al. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells[J]. The Journal of clinical investigation, 2011, 121(4): 1349-1360.
[6] Ishida C T, Shu C, Halatsch M E, et al. Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma[J]. Oncotarget, 2017, 8(23): 37140.
Gamitrinib TPP是一种Gamitrinib（GA）线粒体基质抑制剂[1]。Gamitrinib TPP是一种线粒体靶向HSP90抑制剂，具有抗癌活性，用于化学干扰线粒体蛋白质折叠并诱导线粒体自噬诱导[2, 3]。
在体外，Gamitrinib TPP（10μM）处理稳定表达EGFP-Parkin的HeLa细胞4h和8h，时间依赖性地诱导了Parkin（一种E3泛素连接酶）易位，诱导了线粒体自噬，增加了细胞线粒体中NP40和SDS不溶性蛋白[4]。Gamitrinib TPP（15-20 μM）处理胶质母细胞瘤细胞系（LN229、U251、U87细胞）16h，浓度依赖性地抑制了细胞活力，诱导了线粒体凋亡和自噬[5]。
在体内，Gamitrinib TPP（5mg/kg）通过腹腔注射治疗人类神经胶质瘤异种移植模型小鼠3周，部分抑制了肿瘤生长，与OTX015联合治疗显著抑制了肿瘤生长，并引起肿瘤消退[6]。
| Cas No. | 1131626-46-4 | SDF | |
| Canonical SMILES | O=C(C=C1NC(/C(C)=C/C=C/[C@H](OC)[C@@H](OC(N)=O)/C(C)=C/[C@H](C)[C@H]2O)=O)C(NCCCCCC[P+](C3=CC=CC=C3)(C4=CC=CC=C4)C5=CC=CC=C5)=C(C[C@H](C[C@@H]2OC)C)C1=O | ||
| 分子式 | C52H65N3O8P | 分子量 | 891.06 |
| 溶解度 | Soluble 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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| 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 | 1.1223 mL | 5.6113 mL | 11.2226 mL |
| 5 mM | 0.2245 mL | 1.1223 mL | 2.2445 mL |
| 10 mM | 0.1122 mL | 0.5611 mL | 1.1223 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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2.
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Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy
Oncotarget 2017 Nov 6;8(63):106233-106248.PMID:29290944DOI:10.18632/oncotarget.22287.
Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset Parkinson's disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy. While this pathway is generally accepted to occur upon chemical uncoupling of mitochondria, the (patho-) physiologic relevance has been questioned. However, few studies have indicated that PINK1 and Parkin are also activated upon accumulation of misfolded proteins in the mitochondrial lumen upon overexpression of ΔOTC (Ornithine transcarbamylase). Here, we used the mitochondrial targeted HSP90 inhibitor Gamitrinib-triphenylphosphonium (G-TPP), an anti-cancer agent, to chemically interfere with mitochondrial protein folding. G-TPP treatment induced PINK1 accumulation, ubiquitin phosphorylation at Ser65, Parkin activation and its recruitment to mitochondria was specific for mitochondrial HSP90 inhibition and largely independent of mitochondrial membrane depolarization. Mitophagy induction was observed by monitoring autophagy receptor recruitment and the mitoKeima reporter. Importantly, mitophagy was not only induced in cancer cells but also in primary human fibroblasts and thereof converted neurons. G-TPP treatment might represent a novel strategy to study PINK1 and Parkin-mediated mitochondrial quality control using a more physiologically relevant stress.
Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria
J Biol Chem 2016 Jan 22;291(4):1841-1853.PMID:26631731DOI:10.1074/jbc.M115.656934.
TRAP1 (tumor necrosis factor receptor-associated protein 1), a mitochondrial Hsp90 family chaperone, has been identified as a critical regulator of cell survival and bioenergetics in tumor cells. To discover novel signaling networks regulated by TRAP1, we generated Drosophila TRAP1 mutants. The mutants successfully developed into adults and produced fertile progeny, showing that TRAP1 is dispensable in development and reproduction. Surprisingly, mutation or knockdown of TRAP1 markedly enhanced Drosophila survival under oxidative stress. Moreover, TRAP1 mutation ameliorated mitochondrial dysfunction and dopaminergic (DA) neuron loss induced by deletion of a familial Parkinson disease gene PINK1 (Pten-induced kinase 1) in Drosophila. Gamitrinib-triphenylphosphonium, a mitochondria-targeted Hsp90 inhibitor that increases cell death in HeLa and MCF7 cells, consistently inhibited cell death induced by oxidative stress and mitochondrial dysfunction induced by PINK1 mutation in mouse embryonic fibroblast cells and DA cell models such as SH-SY5Y and SN4741 cells. Additionally, gamitrinib-triphenylphosphonium also suppressed the defective locomotive activity and DA neuron loss in Drosophila PINK1 null mutants. In further genetic analyses, we showed enhanced expression of Thor, a downstream target gene of transcription factor FOXO, in TRAP1 mutants. Furthermore, deletion of FOXO almost nullified the protective roles of TRAP1 mutation against oxidative stress and PINK1 mutation. These results strongly suggest that inhibition of the mitochondrial chaperone TRAP1 generates a retrograde cell protective signal from mitochondria to the nucleus in a FOXO-dependent manner.
Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer
Cancer Lett 2022 Nov 28;549:215915.PMID:36113636DOI:10.1016/j.canlet.2022.215915.
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.
Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses
Cancer Res 2017 Jul 1;77(13):3513-3526.PMID:28522750DOI:10.1158/0008-5472.CAN-16-3424.
Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and Gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of Gamitrinib-TPP. Mechanistic investigations revealed that Gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513-26. ©2017 AACR.
Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide
Exp Ther Med 2021 Nov;22(5):1246.PMID:34539842DOI:10.3892/etm.2021.10681.
Glioma is a common malignant tumor of the central nervous system, accounting for ~50% of intracranial tumors. The current standard therapy for glioma is surgical resection followed by postoperative adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. However, resistance to TMZ is one of the factors affecting prognosis. It has been reported that TNF receptor-associated protein 1 (TRAP1) is overexpressed in numerous types of tumor and that interfering with its function may abrogate chemotherapy resistance. TRAP1 inhibitor Gamitrinib triphenylphosphonium (G-TPP) and shRNA were used in the present study to suppress the function of this molecule in glioblastoma multiforme (GBM) cell lines. MTT assay was performed to evaluate the combined effect of G-TPP and TMZ treatment. To investigate the underlying mechanism responsible for this combined effect, the mitochondrial unfolded protein response (mtUPR), mitophagy, mitochondrial fusion and reactive oxygen species (ROS) were quantified using western blotting and immunofluorescence techniques. TMZ treatment induced apoptosis in GBM cells by activating the p53 pathway, whilst simultaneously downregulating mitophagy and enhancing mitochondrial fusion. The latter may occur in order to compensate for the defect caused by downregulated mitophagy. Suppressing the function of TRAP1 disturbed this compensatory mechanism by inducing mtUPR, which resulted in a burst of ROS formation and sensitized the GBM cells to the effects of TMZ treatment. Thus, suppressing the function of TRAP1 sensitized GBM cells to TMZ lysis by inducing mtUPR and the subsequent ROS burst. TRAP1 is therefore considered to be a promising target for GBM therapy.