title: Pro‑apoptotic effects of pycnogenol on HT1080 human fibrosarcoma cells.
abstract: Complete surgical resection with clear margins remains the mainstay of therapy for localised fibrosarcomas. Nevertheless, metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents like doxorubicin have proven to be effective in <30% of all cases of disseminated fibrosarcoma. Especially elderly patients with cardiac subdisease are not suitable for systemic chemotherapy with doxorubicin. Therefore we tested the apoptotic effects of the well-tolerated pine bark extract pycnogenol and its constituents on human fibrosarcoma cells (HT1080). Ten healthy subjects (six females, four males, mean age 24.8 ± 6 years) received a single dose of 300 mg pycnogenol orally. Blood plasma samples were obtained before and 6 h after intake of pycnogenol. HT1080 cells were treated with these plasma samples. Additionally, HT1080 were incubated separately with catechin, epicatechin and taxifolin that are known as the main constituents of pycnogenol. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarray. The results showed that single application of taxifolin, catechin and epicatechin reduced cell viability of HT1080 cells only moderately. A single dose of 300 mg pycnogenol given to 10 healthy adults produced plasma samples that led to significant apoptotic cell death ex vivo whereas pycnogenol-negative serum displayed no apoptotic activity. Microarray analysis revealed remarkable expression changes induced by pycnogenol in a variety of genes, which are involved in different apoptotic pathways of cancer cells [Janus kinase 1 (JAK1), DUSP1, RHOA, laminin γ1 (LAMC1), fibronectin 1 (FN1), catenin α1 (CTNNA1), ITGB1]. In conclusion, metabolised pycnogenol induces apoptosis in human fibrosarcoma cells. Pycnogenol exhibits its pro-apoptotic activity as a mixture and is more effective than its main constituents catechin, epicatechin and taxifolin indicating that the metabolised components interact synergistically. These results provide experimental support for in vivo trials assessing the effect of the pine bark extract pycnogenol.
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Kamran
authors.initials: K
authors.lastname: Harati
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Slodnik
authors.affiliation: Department of General and Visceral Surgery, St. Josef Hospital, Ruhr‑University Bochum, D‑44791 Bochum, Germany.
authors.forename: Ansgar Michael
authors.initials: AM
authors.lastname: Chromik
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Behr
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Goertz
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hirsch
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Kapalschinski
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Kolbenschlag
authors.affiliation: Department of General and Visceral Surgery, St. Josef Hospital, Ruhr‑University Bochum, D‑44791 Bochum, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Uhl
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lehnhardt
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG‑University Hospital Bergmannsheil, Ruhr‑University Bochum, D‑44789 Bochum, Germany.
authors.forename: Adrien
authors.initials: A
authors.lastname: Daigeler
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010936:Plant Extracts; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010936:Plant Extracts; C024070:pycnogenols; D002392:Catechin; D011794:Quercetin; C003377:taxifolin