Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor
Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor
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DOI：
10.1002/ijc.30097
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发表时间：
2016-08-01
影响因子：
6.4
通讯作者：
Araki, Nobukazu
中科院分区：
文献类型：
--
作者：
Hayashida, Yushi;Ikeda, Yuka;Araki, Nobukazu
XL147 （SAR245408, pilaralisib）是一种具有atp竞争性的泛I类磷酸肌醇3-激酶（PI3K）抑制剂，是一种很有前景的新型抗癌药物。我们在荧光显微镜下检测了PI3K抑制剂对PC3前列腺癌细胞的影响，发现xl147处理的癌细胞在蓝色波长（430 nm）光照射下快速损伤。在辐照过程中，0.2-2 μ M XL147处理的癌细胞出现细胞表面起泡和细胞质空泡化，并在15min内死亡。细胞损伤/死亡程度与XL147剂量和照射光功率有关。这些结果提示XL147可能作为光敏试剂用于癌症的光动力治疗（PDT）。此外，光敏XL147与其他atp竞争性PI3K抑制剂（如LY294002）预处理后的细胞毒作用降低，这表明光敏XL147与细胞中PI3K的结合促进了其细胞毒作用。在使用荧光探针识别活性氧（ROS）的单细胞照明分析中，当细胞被蓝光照射时，观察到xl147处理的细胞中ROS的产生显著增加。综上所述，可以想象在癌细胞中优先积累的XL147可能会被蓝光光敏，产生ROS杀死癌细胞。这项研究将为使用抗癌药物进行PDT开辟新的可能性。
XL147 (SAR245408, pilaralisib), an ATP-competitive pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, is a promising new anticancer drug. We examined the effect of the PI3K inhibitor on PC3 prostate cancer cells under a fluorescence microscope and found that XL147-treated cancer cells are rapidly injured by blue wavelength (430 nm) light irradiation. During the irradiation, the cancer cells treated with 0.2-2 mu M XL147 showed cell surface blebbing and cytoplasmic vacuolation and died within 15 min. The extent of cell injury/death was dependent on the dose of XL147 and the light power of the irradiation. These findings suggest that XL147 might act as a photosensitizing reagent in photodynamic therapy (PDT) for cancer. Moreover, the cytotoxic effect of photosensitized XL147 was reduced by pretreatment with other ATP-competitive PI3K inhibitors such as LY294002, suggesting that the cytotoxic effect of photosensitized XL147 is facilitated by binding to PI3K in cells. In a singlecell illumination analysis using a fluorescent probe to identify reactive oxygen species (ROS), significantly increased ROS production was observed in the XL147-treated cells when the cell was illuminated with blue light. Taken together, it is conceivable that XL147, which is preferentially accumulated in cancer cells, could be photosensitized by blue light to produce ROS to kill cancer cells. This study will open up new possibilities for PDT using anticancer drugs.