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posted on 2023-04-03, 14:46 authored by Karem A. Court, Hiroto Hatakeyama, Sherry Y. Wu, Mangala S. Lingegowda, Cristian Rodríguez-Aguayo, Gabriel López-Berestein, Lee Ju-Seog, Carlos Rinaldi, Eduardo J. Juan, Anil K. Sood, Madeline Torres-Lugo S(A) HSPA6 siRNA gene knock down in vitro by quantitative real-time PCR. HSPA6 expression after gene knockdown in A2780cp20 and HeyA8 using HSPA6 siRNA. (B) Silencing of HSPA6 gene expression in HeyA8 tumor model after 72 hours of siRNA-DOPC injection (n=2). (C) Western Blot of HSP70 protein level in HeyA8 after 30 min MFH heat treatment at 41 and 43ËšC, with recovery time of 1, 4 and 6 hours
Funding
NIH
PR Institute for Functional Nanomaterials
Nanotechnology Center for Biomedical, Environmental and Sustainability Applications
Ovarian Cancer Research Fund
Cancer Prevention and Research Institute of Texas training
History
ARTICLE ABSTRACT
Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calculated for PES treatment reporting a synergistic effect. In vivo efficacy experiments with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly reduction in tumor growth rate was observed with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 intraperitoneal tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966–76. ©2017 AACR.
