Rim Hong-Kun, Cho Sehyeon, Shin Dong-Hyun, Chung Kyung-Sook, Cho Young-Wuk, Choi Jung-Hye, Lee Jae Yeol, Lee Kyung-Tae
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea.
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea.
Molecules. 2014 Jul 8;19(7):9864-75. doi: 10.3390/molecules19079864.
It has been reported that [3-(1,1'-biphenyl-4-yl)-2-(1-methyl-5-dimethylamino-pentylamino)-3,4-dihydroquinazolin-4-yl]-N-benzylacetamide 2hydrochloride (KYS05090), a selective T-type Ca2+ channel blocker, reduces tumor volume and weight in the A549 xenograft model, but the molecular mechanism of cell death has not yet been elucidated. In this study, KYS05090 induced autophagy- and apoptosis-mediated cell death in human lung adenocarcinoma A549 cells. Although KYS05090 decreased intracellular Ca2+ levels, it was not directly related with KYS05090-induced cell death. In addition, KYS05090 generated intracellular reactive oxygen species (ROS) and reduced glucose uptake, and catalase and methyl pyruvate prevented KYS05090-induced cell death. These results indicate that KYS05090 can lead to autophagy and apoptosis in A549 cells through ROS generation by inhibiting glucose uptake. Our findings suggest that KYS05090 has potential chemotherapeutic value for the treatment of lung cancer.
据报道，选择性T型Ca2+通道阻滞剂[3-(1,1'-联苯-4-基)-2-(1-甲基-5-二甲基氨基戊基氨基)-3,4-二氢喹唑啉-4-基]-N-苄基乙酰胺二盐酸盐（KYS05090）可减小A549异种移植模型中的肿瘤体积和重量，但细胞死亡的分子机制尚未阐明。在本研究中，KYS05090诱导人肺腺癌A549细胞发生自噬和凋亡介导的细胞死亡。尽管KYS05090降低了细胞内Ca2+水平，但这与KYS05090诱导的细胞死亡没有直接关系。此外，KYS05090产生细胞内活性氧（ROS）并减少葡萄糖摄取，过氧化氢酶和丙酮酸甲酯可预防KYS05090诱导的细胞死亡。这些结果表明，KYS05090可通过抑制葡萄糖摄取产生ROS，从而导致A549细胞发生自噬和凋亡。我们的研究结果表明，KYS05090在肺癌治疗中具有潜在的化疗价值。
