title: Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum-resistant ovarian cancer cells to paraplatin.
abstract: Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1-4 linkages containing between 2-8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79-479 microg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 microg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 microg/ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells.
authors.affiliation: Department of Plant Biology and Plant Pathology, Rutgers University, New Brunswick, NJ 08019, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Kyu Kwang
authors.initials: KK
authors.lastname: Kim
authors.forename: K S
authors.initials: KS
authors.lastname: Satyan
authors.forename: Roger
authors.initials: R
authors.lastname: Nussbaum
authors.forename: Monica
authors.initials: M
authors.lastname: Torres
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Nicholi
authors.initials: N
authors.lastname: Vorsa
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D029799:Vaccinium macrocarpon / Q000737:chemistry*
chemical_list: D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D044945:Proanthocyanidins; D016190:Carboplatin