title: Targeting of T/Tn antigens with a plant lectin to kill human leukemia cells by photochemotherapy.
abstract: Photochemotherapy is used both for solid tumors and in extracorporeal treatment of various hematologic disorders. Nevertheless, its development in oncology remains limited, because of the low selectivity of photosensitizers (PS) towards human tumor cells. To enhance PS efficiency, we recently covalently linked a porphyrin (TrMPyP) to a plant lectin (Morniga G), known to recognize with high affinity tumor-associated T and Tn antigens. The conjugation allowed a quick uptake of PS by Tn-positive Jurkat leukemia cells and efficient PS-induced phototoxicity. The present study was performed: (i) to evaluate the targeting potential of the conjugate towards tumor and normal cells and its phototoxicity on various leukemia cells, (ii) to investigate the mechanism of conjugate-mediated cell death. The conjugate: (i) strongly increased (×1000) the PS phototoxicity towards leukemic Jurkat T cells through an O-glycan-dependent process; (ii) specifically purged tumor cells from a 1∶1 mixture of Jurkat leukemia (Tn-positive) and healthy (Tn-negative) lymphocytes, preserving the activation potential of healthy lymphocytes; (iii) was effective against various leukemic cell lines with distinct phenotypes, as well as fresh human primary acute and chronic lymphoid leukemia cells; (iv) induced mostly a caspase-independent cell death, which might be an advantage as tumor cells often resist caspase-dependent cell death. Altogether, the present observations suggest that conjugation with plant lectins can allow targeting of photosensitizers towards aberrant glycosylation of tumor cells, e.g. to purge leukemia cells from blood and to preserve the normal leukocytes in extracorporeal photochemotherapy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR 1037, Equipe 4, Centre de Recherches en Cancérologie de Toulouse, CHU Rangueil, BP84225, 31432 Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Poiroux
authors.forename: Marguerite
authors.initials: M
authors.lastname: Pitié
authors.forename: Raphaël
authors.initials: R
authors.lastname: Culerrier
authors.forename: Elodie
authors.initials: E
authors.lastname: Lafont
authors.forename: Bruno
authors.initials: B
authors.lastname: Ségui
authors.forename: Els J M
authors.initials: EJ
authors.lastname: Van Damme
authors.forename: Willy J
authors.initials: WJ
authors.lastname: Peumans
authors.forename: Jean
authors.initials: J
authors.lastname: Bernadou
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Pierre
authors.initials: P
authors.lastname: Rougé
authors.forename: Annick
authors.initials: A
authors.lastname: Barre
authors.forename: Hervé
authors.initials: H
authors.lastname: Benoist
mesh_terms: D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D037121:Plant Lectins / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology; D020298:U937 Cells
chemical_list: C569826:5-(4-(5-carboxy-1-butoxy)phenyl)-10,15,20-tris(4-N-methyl)pyridiniumylporphyrin; D015295:Antigens, Tumor-Associated, Carbohydrate; D017319:Photosensitizing Agents; D037121:Plant Lectins; D011166:Porphyrins; C040286:Tn antigen; C569827:morniga G protein, Morus nigra; D020169:Caspases