title: Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of cell death by necrosis.
abstract: The anti-malarial drug chloroquine (CQ) is also thought to be a potential radiation sensitizer. To gain a better understanding of how the lysomotropic CQ can potentiate the effects of ionizing radiation, we investigated the effects of CQ on lysosomal and mitochondrial membrane stability, the subcellular localization of ceramide, plasma membrane permeability, and the mode of cell death in response to irradiation. We found that CQ accumulated in the lysosomes and thus lysosomal volumes increased. As a result, both the lysosomal and plasma membranes were destabilized. After 7 Gy irradiation, most ceramide was associated with the lysosomes in the cells treated with CQ but not in the CQ-untreated control. The elevated levels of ceramide in the lysosomes of the CQ-treated cells appeared to further destabilize the lysosomal and plasma membranes of the cell. Both CQ-treated and -untreated cells had approximately the same rate of cell death by apoptosis after 7 Gy irradiation (P > 0.05, ns). However, in contrast to the CQ-untreated control, the CQ-treated cells underwent massive cell death by necrosis at 24-48 h after irradiation (P < 0.05). Taken together, our data support the idea that the increase in cytotoxic effects by the combination of CQ and radiation is due to radiation-mediated apoptosis and CQ-mediated necrosis.
authors.affiliation: Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario P3E 5J1, Canada. hlee@hrsrh.on.ca
authors.forename: Helen
authors.initials: H
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Cai
authors.forename: Stacey
authors.initials: S
authors.lastname: Santi
authors.forename: Robert
authors.initials: R
authors.lastname: Lafrenie
authors.forename: Hoyun
authors.initials: H
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D008247:Lysosomes / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D008560:Membrane Fluidity / Q000187:drug effects / Q000528:radiation effects; D009336:Necrosis / Q000473:pathology; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage
chemical_list: D011838:Radiation-Sensitizing Agents; D002738:Chloroquine