Iron-oxide nanoparticles target intracellular HSP90 to induce tumor radio-sensitization

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 5; pp. 857 - 869
• Main Authors: Shetake, Neena G., Kumar, Amit, Pandey, Badri N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2019
• Subjects: Apoptosis; cell cycle checkpoints; cell proliferation; cyclins; DNA damage; drug therapy; fever; fibrosarcoma; gamma radiation; growth models; HSP90; humans; Iron oxide nanoparticles; iron oxides; magnetism; mice; mitosis; Mitotic catastrophe; nanoparticles; Tumor radiosensitization; tumor suppressor proteins; PBS; HSP90; H&E; Tumor radiosensitization; DAPI; BRCA1; MTT; SiRNA; CDC2; SDS-PAGE; TUNEL; Iron oxide nanoparticles; PMSF; FCS; Mitotic catastrophe; SEM; GAPDH; Apoptosis
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.02.010

Nanoparticle-based therapies have emerged as a promising approach to overcome limitations of conventional chemotherapy. Present study investigates the potential of oleic acid-functionalized iron-oxide nanoparticles (MN-OA) to enhance the radiation response of fibrosarcoma tumor and elucidates its underlying mechanism. Various cellular and molecular assays (e.g. MTT, clonogenic, cell cycle analysis, cell death, DNA damage/repair) and tumor growth kinetics were employed to investigate the mechanism of MN-OA induced radio-sensitization. Mouse (WEHI-164) and human (HT-1080) fibrosarcoma cells treated with MN-OA and gamma-radiation (2 Gy) showed a significant decrease in the cell proliferation. Combination treatment showed significant decrease in clonogenic survival of WEHI-164 cells and was found to induce cell cycle arrest, apoptosis and mitotic catastrophe. The mechanism of radio-sensitization was found to involve binding of MN-OA with HSP90, resulting in down-regulation of its client proteins, involved in cell cycle progression (Cyclin B1 and CDC2) and DNA-double strand break repair (e.g. RAD51 and BRCA1). Consistently, longer persistence of DNA damage in cells treated with MN-OA and radiation was observed in the form of γ-H2AX foci. The efficacy and mechanism of MN-OA-induced radio-sensitization was also validated in an immuno-competent murine fibrosarcoma model. This study reveals the key role of HSP90 in the mechanism of tumor radio-sensitization by MN-OA. Present work provides a deeper understanding about the mechanism of MN-OA-induced tumor radiosensitization, highlighting the role of HSP90 protein. In addition to diagnostic and magnetic hyperthermia abilities, present remarkable radiosensitizing activity of MN-OA would further excite the clinicians to test its anti-cancer potential. [Display omitted] •MN-OA significantly improved radiosensitivity of fibrosarcoma cells and its tumor.•MN-OA enhanced radiation-induced DNA damage, mitotic catastrophe and apoptosis.•The mechanism was found to be mediated by binding of MN-OA with HSP90.•A tumor growth delay index of 2.1 was observed by MN-OA plus gamma-radiation.•HSP90 seemed to be a key target for MN-OA-mediated tumor radiosensitization.