Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase
Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase
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DOI：
10.1007/s00018-015-1902-6
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发表时间：
2015-10-01
影响因子：
8
通讯作者：
Kiss, Robert
中科院分区：
文献类型：
--
作者：
Mathieu, Veronique;Chantome, Aurelie;Kiss, Robert
尽管近年来在治疗具有内在化疗耐药的肿瘤方面取得了进展，如黑色素瘤和肾癌，但其预后仍然很差，迫切需要新的有希望治疗这些癌症的化学药物。Sphaeropsidin A是一种真菌代谢物，其抗癌潜力以前很少受到关注，从柏树双倍体中分离出来，在美国国家癌症研究所（NCI）的60个细胞系筛选中发现，Sphaeropsidin A在体外对黑色素瘤和肾癌亚组显示出特定的抗癌活性。NCI数据显示，平均LC50约为10 μ M，细胞敏感性谱与765,000种化合物数据库中的任何其他药物都不匹配。随后在黑色素瘤和其他多药耐药的体外癌症模型中的机制研究表明，sphaeropsidin A可以通过诱导细胞内Cl-的丢失和培养上清中HCO3（-）浓度的降低而显著和快速的细胞收缩来克服细胞凋亡和多药耐药。这些离子稳态的变化和对质膜电位的无影响归因于球藻苷a诱导的调节体积增加（RVI）的损害。初步结果还表明，根据不同的癌症类型，球藻sidin A对RVI的作用可能与Na-K-2Cl电中性共转运体或Cl-/HCO3（-）阴离子交换剂(s)靶向有关。本研究强调了离子转运体活性的调节是对抗耐药癌症的一种有前景的治疗策略，并确定了真菌代谢物sphaeropsidin a作为开发针对癌细胞RVI的抗癌药物的先导。
Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 A mu M and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl- and the decreased HCO3 (-) concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na-K-2Cl electroneutral cotransporter or Cl-/HCO3 (-) anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells.