title: Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer.
abstract: In this study, we evaluated the effects of protopanaxadiol (PPD), a gut microbiome induced ginseng metabolite, in increasing the anticancer effects of a chemotherapeutic agent fluorouracil (5-FU) on colorectal cancer. An in vitro HCT-116 colorectal cancer cell proliferation test was conducted to observe the effects of PPD, 5-FU and their co-administration and the related mechanisms of action. Then, an in vivo xenografted athymic mouse model was used to confirm the in vitro data. Our results showed that the human gut microbiome converted ginsenoside compound K to PPD as a metabolite. PPD and 5-FU significantly inhibited HCT-116 cell proliferation in a concentration-dependent manner (both p<0.01), and the effects of 5-FU were very significantly enhanced by combined treatment with PPD (p<0.01). Cell cycle evaluation demonstrated that 5-FU markedly induced the cancer cell S phase arrest, while PPD increased arrest in G1 phase. Compared to the control, 5-FU and PPD increased apoptosis, and their co-administration significantly increased the number of apoptotic cells (p<0.01). Using bioluminescence imaging, in vivo data revealed that 5-FU significantly reduced the tumor growth up to Day 20 (p<0.05). PPD and 5-FU co-administration very significantly reduced the tumor size in a dose-related manner (p<0.01 compared to the 5-FU alone). The quantification of the tumor size and weight changes for 43 days supported the in vivo imaging data. Our results demonstrated that the co-administration of PPD and 5-FU significantly inhibited the tumor growth, indicating that PPD significantly enhanced the anticancer action of 5-FU, a commonly used chemotherapeutic agent. PPD may have a clinical value in 5-FU's cancer therapeutics.
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. czwang@uchicago.edu.
authors.forename: Chong-Zhi
authors.initials: CZ
authors.lastname: Wang
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. zzhang2@bsd.uchicago.edu.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. wanjinyi1128@163.com.
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Wan
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. zhangchunfeng67@163.com.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Zhang
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. sanderson6@uchicago.edu.
authors.forename: Samantha
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. xhe@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. yuch@hyit.edu.cn.
authors.forename: Chunhao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Orthopedic Surgery, University of Chicago, Chicago, IL 60637, USA. tche@bsd.uchicago.edu.
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. fleude@126.com.
authors.forename: Lian-Wen
authors.initials: LW
authors.lastname: Qi
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA. cyuan@dacc.uchicago.edu.
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D005894:Panax / Q000737:chemistry; D012502:Sapogenins / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D012502:Sapogenins; C062916:protopanaxadiol; D005472:Fluorouracil