Concanamycin A

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].

References:
[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]。