Interaction of ionizing radiation and ZRBA1, a mixed EGFR/DNA-targeting molecule.
ZRBA1 is a molecule termed 'combi-molecule' designed to induce DNA-alkylating lesions and to block epidermal growth factor receptor (EGFR) tyrosine kinase. Owing to its ability to downregulate the EGFR tyrosine kinase-mediated antiapoptotic signaling and DNA repair proteins, we inferred that it could significantly sensitize cells to ionizing radiation. Using the MDA-MB-468 human breast cancer cell line in which ZRBA1 has already been reported to induce significant EGFR/DNA-targeting potency, the results showed that: (i) concurrent administration of ZRBA1 and 4 Gy radiation led to a significant decrease in cell viability, (ii) the greater efficacy of the combination was sequential, being limited to conditions wherein the drug was administered concurrently with radiation or before radiation, and (iii) the efficacy enhancement of the combination was further confirmed by clonogenic assays from which a dose enhancement factor of 1.34 could be observed at survival fraction of 0.01. Flow cytometric analysis showed significant enhancement of cell cycle arrest in G2/M (P<0.046, irradiated cells vs. cells treated with ZRBA1 and radiation) and increased apoptosis when ZRBA1 was combined with radiation. Likewise, significant levels of double-strand breaks were observed for the combination, as determined by neutral comet assay (P<0.045, irradiated cells vs. cells treated with ZRBA1 and radiation). These results in toto suggest that the superior efficacy of the ZRBA1 plus radiation combination may be secondary to the ability of ZRBA1 to arrest the cells in G2/M, a cell cycle phase in which tumor cells are sensitive to radiation. Furthermore, the increased levels of DNA damage, combined with the concomitant downregulation of EGFR-mediated signaling by ZRBA1, may account for the significant levels of cell killing induced by the combination.
Heravi
Mitra
M
Department of Human Genetics, Cancer Drug Research Laboratory, McGill University, Montreal, Quebec H3T 1E2, Canada.
Rachid
Zakaria
Z
Goudarzi
Atta
A
Schlisser
Ava
A
Jean-Claude
Bertrand J
BJ
Radzioch
Danuta
D
Muanza
Thierry M
TM
D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D008856:Microscopy, Fluorescence; D011799:Quinazolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000528:radiation effects; D014226:Triazenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D014965:X-Rays
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D014226:Triazenes; C503825:ZRBA1 compound; D066246:ErbB Receptors; D000077156:Gefitinib