title: Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.
abstract: Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.
authors: Molecular Genetics Program, Jenomic, Carmel, California, USA. dst@sbcglobal.net
authors: David S
authors: DS
authors: Terman
authors: Benjamin L
authors: BL
authors: Viglianti
authors: Rahima
authors: R
authors: Zennadi
authors: Diane
authors: D
authors: Fels
authors: Richard J
authors: RJ
authors: Boruta
authors: Hong
authors: H
authors: Yuan
authors: Mathew R
authors: MR
authors: Dreher
authors: Gerald
authors: G
authors: Grant
authors: Zahid N
authors: ZN
authors: Rabbani
authors: Ejung
authors: E
authors: Moon
authors: Lan
authors: L
authors: Lan
authors: Joseph
authors: J
authors: Eble
authors: Yiting
authors: Y
authors: Cao
authors: Brian
authors: B
authors: Sorg
authors: Kathleen
authors: K
authors: Ashcraft
authors: Greg
authors: G
authors: Palmer
authors: Marilyn J
authors: MJ
authors: Telen
authors: Mark W
authors: MW
authors: Dewhirst
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000276:immunology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004913:Erythrocytes, Abnormal / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia; D016219:Immunotherapy, Adoptive; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D008565:Membrane Proteins; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; D006427:Hemin; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse