A plecomacrolide antibiotic
Concanamycin A is a specific inhibitor of vacuolar-type ATPase (V-ATPase) with IC50 value of 10 nM [1].
Vacuolar-type ATPase (V-ATPase) is expressed by clear cells to acidify the lumen of the epididymis, which is essential for male fertility; what's more, it induced proton extrusion into the extracellular medium which contributes to maintaining the intracellular pH under an acidic microenvironment. V-ATPase has also been reported to involve in the process of acidificating microenvironment around/in solid tumors and inducing tumor invasion/multi-drug resistance in several malignant tumors. [2].
Concanamycin A (CMA) is a specific V-ATPase inhibitor and is different from the reported V-ATPase inhibitor SS33410. In oral squamous cell carcinoma (OSCC) OSCC cell lines (MISK81-5, SAS and HSC-4), low-concentration of CMA treatment induced the apoptosis of tumor cells [3]. Pretreated colorectal cancer cell lines with concanamycin A could significantly enhanced the Tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL)-induced apoptosis by blocking endosomal acidification by V-ATPase [4]. When tested with prostate cancer cell line C4-2B, inhibition of V-ATPase by concanamycin A reduced 80% invasion in vitro [5].
Concanamycin A also had been reported as a potent inhibitor of CTL cytotoxicity via perforin-mediated cytotoxic pathway [6].
参考文献:
[1].? Huss, M., et al., Concanamycin A, the specific inhibitor of V-ATPases, binds to the V(o) subunit c. J Biol Chem, 2002. 277(43): p. 40544-8.
[2].? Muroi, M., et al., Folimycin (concanamycin A), a specific inhibitor of V-ATPase, blocks intracellular translocation of the glycoprotein of vesicular stomatitis virus before arrival to the Golgi apparatus. Cell Struct Funct, 1993. 18(3): p. 139-49.
[3].? Kiyoshima, T., et al., Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression. PLoS One, 2013. 8(11).
[4].? Horova V, et al., Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. FEBS J, 2013. 280(14).
[5].? Michel V, et al., Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. Int J Cancer. 2013.132(2).
[6].? Benkhoucha M et al., The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. J Neuroinflammation. 2013, 10.
Concanamycin A 是液泡型 ATP 酶 (V-ATPase) 的特异性抑制剂，IC50 值为 10 nM [1]。
液泡型 ATP 酶 (V-ATPase) 由透明细胞表达以酸化附睾腔，这对男性生育能力至关重要；更重要的是，它诱导质子挤出到细胞外介质中，这有助于在酸性微环境下维持细胞内 pH 值。据报道，V-ATPase 还参与实体瘤周围/内部微环境的酸化过程，并在多种恶性肿瘤中诱导肿瘤侵袭/多药耐药。 [2].
刀豆霉素 A (CMA) 是一种特异性 V-ATPase 抑制剂，与报道的 V-ATPase 抑制剂 SS33410 不同。在口腔鳞状细胞癌 (OSCC) OSCC 细胞系（MISK81-5、SAS 和 HSC-4）中，低浓度的 CMA 处理可诱导肿瘤细胞凋亡 [3]。用刀豆霉素 A 预处理的结直肠癌细胞系可通过阻断 V-ATP 酶的内体酸化，显着增强肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 诱导的细胞凋亡 [4]。当用前列腺癌细胞系 C4-2B 进行测试时，刀豆霉素 A 对 V-ATPase 的抑制作用使体外侵袭降低了 80% [5]。
刀豆霉素 A 也被报道为通过穿孔素介导的细胞毒性途径的 CTL 细胞毒性的有效抑制剂 [6]。
| Cell experiment [1,2]: | |
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Cell lines |
HCT-116, DLD-1, Colo206F, HeLa cells, Androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells. |
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Preparation method |
This compound is limited soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
20 nM, 60 min |
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Applications |
CCA effectively attenuated the TRAIL-induced activation of caspases in TRAIL-sensitive colorectal cancer cell lines. In CCA-treated Colo206F cells, the number of M30-positive apoptotic cells gradually increased and almost reached the proportion seen in untreated cells within 3–4h after the addition of TRAIL. Treatment with CCA resulted in a lack of apoptosis-related chromatin condensation in DLD-1 cells incubated with TRAIL for 90 min. Treatment with nanomolar concentrations of concanamycin A reduced the in vitro invasion in LNCaP and C4-2B cell types by 80%. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Horova V, et al., Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. FEBS J, 2013. 280(14). [2]. Michel V, et al., Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. Int J Cancer. 2013.132(2). |
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