Phthalazino[1,2‑b]quinazolinones
as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak–Bcl-xl
Complex Reorganization in Bladder Cancer Cells
posted on 2017-07-26, 00:00authored byGuo-Hai Zhang, Jing-Mei Yuan, Gang Qian, Chen-Xi Gu, Kai Wei, Dong-Liang Mo, Jiang-Ke Qin, Yan Peng, Zu-Ping Zhou, Cheng-Xue Pan, Gui-Fa Su
p53 inactivation
is a clinically defined characteristic for cancer
treatment-nonresponsiveness. It is therefore highly desirable to develop
anticancer agents by restoring p53 function. Herein the synthesized phthalazino[1,2-b]quinazolinones
were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as
the most promising candidate in view of both its anticancer activity
and mechanisms of action. 5da exhibited strong anticancer
activity on a broad range of cancer cell lines and significantly reduced
tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore, 5da caused cell cycle arrest at S/G2 phase, induced apoptosis,
changed cell size, and led to cell death by increasing the proportion
of sub-G1 cells. Molecular mechanism studies suggested that accumulation
of phospho-p53 in mitochondria after 5da treatment resulted
in conformational activation of Bak, thereby evoking cell apoptosis,
finally leading to irreversible cancer cell inhibition. Our present
studies furnish new insights into the molecular interactions and anticancer
mechanisms of phospho-p53-dependent quinazolinone compound.