title: Pseudolaric acid B induces mitotic arrest and apoptosis in both 5-fluorouracil-sensitive and -resistant colorectal cancer cells.
abstract: 5-fluorouracil (5-FU)-based chemotherapy is the main chemotherapeutic approach for colorectal cancer (CRC) treatment. Because chemoresistance occurs frequently and significantly limits CRC therapies, a novel agent is needed. Pseudolaric acid B (PAB), a small molecule derived from the Chinese medicinal herb ''Tujinpi'', exhibits strong cytotoxic effects on a variety of cancers. However, the detailed mechanisms by which PAB inhibits CRC cell growth and its potential role in overcoming 5-FU resistance have not been well studied. In this study, we showed that PAB significantly inhibited the viability of various CRC cell lines but induced minor cytotoxicity in normal cells. Both the in vitro and in vivo results showed that PAB induced proliferation inhibition, mitotic arrest and subsequently caspase-dependent apoptosis in both 5-FU-sensitive and -resistant CRC cells. Moreover, PAB was shown to interfere with CRC cell mitotic spindle apparatus and activate the spindle assembly checkpoint. Finally, CDK1 activity was involved in PAB-induced mitotic arrest and apoptosis in CRC cells. Taken together, these data reveal that PAB induces CRC cell mitotic arrest followed by apoptosis and overcomes 5-FU resistance in vitro and in vivo, suggesting that PAB may be a potential agent for CRC treatment, particularly for 5-FU-resistant CRC.
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chuangyu
authors.initials: C
authors.lastname: Wen
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Junxiong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Che
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: He
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zerong
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Lin
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lou
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Daici
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Donglin
authors.initials: D
authors.lastname: Ren
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lan
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China. Electronic address: liuhuanl@mail.sysu.edu.cn.
authors.forename: Huanliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: yangxl28@mail.sysu.edu.cn.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; C058391:pseudolaric acid B; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D020169:Caspases; D005472:Fluorouracil
keywords: 5-FU resistance; Apoptosis; Colorectal cancer; Mitotic arrest; Pseudolaric acid B; Spindle