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.
Highlights
Hyperthermia is the application of heat to tissues as a therapeutic tool using temperatures between 41C and 47C
There is evidence that Magnetic fluid hyperthermia (MFH) can deliver heat more efficiently than conventional hyperthermia [6,7,8,9,10,11,12]. Aspects such as thermal chemosensitization, membrane permeabilization, and sensitization of drug-resistant cancer cells have been observed as responses to MFH in vitro [2, 7,8,9]. These findings demonstrate that MFH has potential as an adjuvant cancer treatment, but there is still a dearth of knowledge in the field regarding the implications of MFH at the molecular level and how these can be exploited to enhance the effects of MFH in cancer treatment
MFH in ovarian cancer cell lines Four ovarian cancer cell lines, A2780 and HeyA8, and their corresponding drug resistant sub-lines were exposed to MFH at various temperatures (41C, 43C, and 45C) and exposure times (30 or 60 minutes)
Summary
Hyperthermia is the application of heat to tissues as a therapeutic tool using temperatures between 41C and 47C. Hyperthermia has been successfully employed as an adjuvant for the treatment of several cancers and is known to enhance the effects of chemotherapy and radiotherapy [1,2,3]. Heat can be applied locally, regionally or in the whole-body, but current modalities are not site specific [1, 4]. Challenges such as temperature homogeneity during application, achieving an efficient heat. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Magnetic fluid hyperthermia (MFH) is an attractive alternative as it can deliver heat to the desired area using magnetic nanoparticles under the influence of a magnetic field [1, 2, 5]
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