Abstract
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.
Highlights
IntroductionCalcium is an essential signal transduction element in the progression of the cell cycle [1]
Calcium is an essential signal transduction element in the progression of the cell cycle [1].Controlling intracellular Ca2+ ([Ca2+]i) is crucial for the orderly progression of the cell cycle and plays a vital role in the regulation of cell proliferation and growth [2]
To identify the molecular mechanism underlying cell death induced by KYS05090, the translocation of phosphatidylserine was assessed using Annexin V and propidium iodide (PI) double staining by flow cytometry
Summary
Calcium is an essential signal transduction element in the progression of the cell cycle [1]. The T-type Ca2+ channel has been reported to be involved in pacemaker activity, pain processing, and tumor pathophysiology [4,5]. Previous studies have reported that the T-type Ca2+ channel is expressed in cancerous cells, and several evidences have provided new insights into the development of T-type Ca2+ channel blockers in cancer therapy [5,6,7]. Our previous studies have indicated that KYS05047, a T-type Ca2+ channel blocker, induces G1 phase cell cycle arrest in A549 cells associated with a decrease in [Ca2+]i and that both KYS05047 and KYS05090 show potent in vivo antitumor activity against the A549 xenograft mice [8,9]. The present study examines the molecular mechanism of KYS05090 underlying cell death in A549 cells
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