title: Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy.
abstract: In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: James
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Chinenye
authors.initials: C
authors.lastname: Iwuji
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Glen
authors.initials: G
authors.lastname: Irving
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Ankur
authors.initials: A
authors.lastname: Karmokar
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Higgins
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Griffin-Teal
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Greaves
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Samita R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Morgan
authors.affiliation: Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Dennison
authors.affiliation: Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Metcalfe
authors.affiliation: Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Garcea
authors.affiliation: Department of Hepatobiliary Surgery, Leicester General Hospital, Gwendolen Road, Leicester, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Lloyd
authors.affiliation: Department of Hepatobiliary Surgery, University Hospitals of Wales, Cardiff, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Berry
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK. Electronic address: lh28@le.ac.uk.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Howells
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D064593:Heterografts; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D018874:Spheroids, Cellular
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003474:Curcumin; D002955:Leucovorin; D005472:Fluorouracil
keywords: Cancer stem cells; Colorectal liver metastases; Combination therapy; Curcumin