In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

  • J Med Chem. 2019 Feb 14;62(3):1541-1561. doi: 10.1021/acs.jmedchem.8b01742.
Xin-Ya Xu  1 ,  Siu Wai Tsang  1 ,  Yi-Fu Guan  1 ,  Kang-Lun Liu  1 ,  Wen-Hui Pan  1 ,  Chu Shing Lam  1 ,  Kwan Ming Lee  1 ,  Yi-Xuan Xia  1 ,  Wen-Jian Xie  1 ,  Wing Yan Wong  2 ,  Magnolia Muk Lan Lee  2 ,  William Chi Shing Tai  2 ,  Hong-Jie Zhang  1
Affiliations
  • 1. Teaching and Research Division, School of Chinese Medicine , Hong Kong Baptist University , 7 Baptist University Road , Kowloon Tong , Hong Kong SAR , People's Republic of China.
  • 2. Department of Applied Biology and Chemical Technology , The Hong Kong Polytechnic University , Hung Hom , Hong Kong SAR , People's Republic of China.
PMID: 30633861 DOI: 10.1021/acs.jmedchem.8b01742
Abstract

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as Anticancer lead molecules. In the present study, we isolated 19 miliusanes (1-19), including 11 novel ones (5 and 10-19) from another Miliusa plant ( M. balansae), and synthesized additional derivatives to elucidate the structure-activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5-40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their Anticancer mechanism, 1-3 (GI50 0.03-4.79) were administered to a wide spectrum of human Cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.