title: Hoechst 33342 induces radiosensitization in malignant glioma cells via increase in mitochondrial reactive oxygen species.
abstract: Mitochondrial DNA plays an important role in cellular sensitivity to cancer therapeutic agents. Hoechst 33342, a DNA minor groove binding ligand, has shown radiosensitizing effects in different cancer cell lines. In the present study, the possible binding of Hoechst 33342 with mitochondrial DNA, isolated from human cerebral glioma (BMG-1) cells, was investigated and consequences of this binding on excessive reactive oxygen species (ROS) generation in irradiated BMG-1 cells were studied. Alteration in the fluorescence spectroscopic characteristics of Hoechst 33342 suggested binding of Hoechst 33342 with isolated mitochondria and mitochondrial DNA. Persistent increase in level of ROS in the presence of Hoechst 33342 has been observed, which was further enhanced in irradiated cells. Investigations using inhibitors of ETC complex I suggested that mitochondrial bound Hoechst 33342 contributed to increased ROS, which was associated with alteration in DeltaPsim and antioxidant machinery. These factors appeared to contribute in potentiating radiation-induced cell death in BMG-1 cells. The finding from these studies will be useful in designing better anti-cancer strategies.
authors.affiliation: Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Brig. S. K. Mazumdar Road, Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.forename: Nabo K
authors.initials: NK
authors.lastname: Chaudhury
authors.forename: Mohammad E
authors.initials: ME
authors.lastname: Hussain
authors.forename: Rajeev
authors.initials: R
authors.lastname: Varshney
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000302:isolation & purification / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004272:DNA, Mitochondrial; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D012402:Rotenone; C007517:diphenyleneiodonium; C017807:bisbenzimide ethoxide trihydrochloride