title: Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents.
abstract: Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Pharmacognosy Division, Medical College of Chinese People's Armed Police Force, Tianjin 300162, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Cao
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China.
authors.forename: Hai
authors.initials: H
authors.lastname: Shang
authors.affiliation: Pharmacognosy Division, Medical College of Chinese People's Armed Police Force, Tianjin 300162, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Niu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Zhong-Heng
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Tianjin First Central Hospital, Tianjin 300192, PR China.
authors.forename: Dan-Li
authors.initials: DL
authors.lastname: Tian
authors.affiliation: Pharmacognosy Division, Medical College of Chinese People's Armed Police Force, Tianjin 300162, PR China.
authors.forename: Shi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pharmacognosy Division, Medical College of Chinese People's Armed Police Force, Tianjin 300162, PR China; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: chenhongtian06@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China. Electronic address: zmzou@implad.ac.cn.
authors.forename: Zhong-Mei
authors.initials: ZM
authors.lastname: Zou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018432:Drug Resistance, Multiple / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D011034:Podophyllotoxin
keywords: Apoptosis; Cytotoxicity; MDR-1; Multidrug resistance; Podophyllotoxin