OncoTargets and Therapy (Jan 2018)
Combination of betulinic acid with diazen-1-ium-1,2-diolate nitric oxide moiety donating a novel anticancer candidate
Abstract
Laiyin Zhang,1 Shuangxing Hou,2 Bo Li,3 Jianjian Pan,4 Liping Jiang,5 Guiying Zhou,2 Hong Gu,6 Caixing Zhao,6 Huiping Lu,6 Fenfen Ma6 1Department of Pharmacy, Linyi People’s Hospital, Linyi, 2Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 3Department of Hand Surgery, Huashan Hospital, Fudan University, 4Department of General Medicine, Fudan University, 5Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, 6Department of Pharmacy, Pudong Hospital, Fudan University, Shanghai, China Background: Betulinic acid (BA) is a complex lupane triterpenoid with unique antineoplastic activity. However, its antiproliferative activity is far from satisfaction. In order to improve its anticancer efficacy, betulinic acid was conjugated with a nitric oxide (NO)-releasing moiety to get a novel hybrid, BA-78. Methods: The antiproliferative activity of BA-78 against 6 cell lines and the ability of releasing nitric oxide were determined. The pro-apoptosis mechanism of BA-78 was investigated as well. Results: BA-78 exhibited time-dependent release of NO, and it displayed higher antiproliferative potential than BA through increasing apoptosis and inducing cell cycle arrest at G1 phase. Western blotting results showed that BA-78 increased the expression of Bax, Bid, Bad and cytochrome C and reduced the level of anti-apoptosis proteins including Bcl-2 and Bcl-xl. Conclusion: Our study revealed that novel compound BA-78, possessing betulinic acid and nitric oxide (NO)-releasing moiety, could be developed as an antitumor agent. Keywords: lupane triterpenoid, nitric oxide, anticancer, apoptosis, NONOate, Bcl-2 family
