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Autophagy:肿瘤酸性pH值抑制氯喹的抗癌功效

来源:生物谷 2014-02-12 22:01

2014年2月12日讯 /生物谷BIOON/--据来自瑞典卡罗林斯卡医学院一项最新研究证实:肿瘤的低pH值是抵消药物氯喹治疗癌症理想效果的罪魁祸首。结果发表在杂志Autophagy上,或许可以解释氯喹在临床研究中缺乏疗效的原因。

氯喹,一种广泛使用的抗疟疾药物,目前正在临床试验中被研究调查对癌症患者的治疗效果。氯喹抑制肿瘤细胞自噬的能力已经引起了研究人员的兴趣。

自噬是一个稳态过程,细胞“吃”自己的部分,使得受损或不必要的细胞器和有毒蛋白质被分解和回收。

在缺乏营养物质情况下,细胞诉诸自噬来获得生存。通过这种方式,自噬帮助癌细胞在营养成分不足、低氧和酸性pH环境下生存。

此外,肿瘤细胞使用自噬,以保护自己免受各种形式的抗癌疗法,包括化疗。几项研究已经表明,抑制自噬常常增加肿瘤细胞的化疗敏感性和放射敏感性。

因此,氯喹结合现有的癌症治疗被认为是一个很有前途的治疗战略。然而,在某些癌症模型中,氯喹似乎不能阻止自噬作用,其机制还没有被确定。

在本研究中,科学家研究癌细胞或培养在酸性pH环境中很短时间,或适于慢性酸中毒情况下,氯喹对不同癌症细胞的作用,研究人员还研究了其对小鼠肿瘤生长的效果。

Angelo De Milito表示:我们发现,肿瘤细胞代谢改变,组织酸化是氯喹缺乏抗自噬活性的主要原因。(生物谷Bioon.com)

 

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Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine; Implications for cancer therapies

Paola Pellegrini, Angela Strambi, Chiara Zipoli, Maria H?gg-Olofsson, Maria Buoncervello, Stig Linder, Angelo De Milito.

Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.

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