Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair

Abstract

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be clinically effective, but the mechanisms by which hyperthermia enhances the sensitivity of cells to chemotherapeutic drugs has not yet been elucidated. Methods:To identify the key molecules involved in thermochemotherapy, this study used mass spectrometry (MS)-based quantitative proteomics technology to analyze the effects of thermochemotherapy on the heat-sensitive ovarian cancer cell line A2780. We divided the A2780 cell line into four groups, one group served as blank control, and the other three groups were stimulated by oxaliplatin, stimulated by hyperthermia at 42 ℃, and stimulated by hyperthermia combined with oxaliplatin. Samples were then collected for tandem mass tag (TMT) labeling, high-performance liquid chromatography fractionation, and MS-based quantitative proteomics for analysis The differentially expressed proteins were quantitatively compared and identified, and Gene Ontology (GO) assessment and cluster analyses were performed. Finally, the above MS results were verified again by Western blotting experiments.Results: A total of 349 differentially expressed proteins were identified between cells treated with chemotherapy alone (group B) and cells treated with a combination of chemotherapy and hyperthermia (group D). There were 145 upregulated proteins and 204 downregulated proteins. Among the top 20 proteins with significantly different expression levels, nearly two-thirds were involved in DNA damage repair. These proteins were subsequently verified by Western blot analysis. Indeed, consistent with MS data, the expression of the RBL1 protein was significantly upregulated in cells treated with thermochemotherapy (group D) compared to cells treated with chemotherapy alone (group B). Conclusions:In heat-sensitive ovarian cancer cells, the damage repair of tumor cell DNA is disturbed by hyperthermia, making it unable to fully repair when damaged by chemotherapeutic drugs. As a result, hyperthermia enhances the efficacy of chemotherapeutic drugs. RBL1, as a tumor suppressor gene, may be associated with the repair of DNA damage, and thus it may be a key target for hyperthermia to enhance the sensitivity of thermosensitive cells to chemotherapeutic drugs.

Combination Therapy of Radiation and Hyperthermia, Focusing on the Synergistic Anti-Cancer Effects and Research Trends

“…These synergistic effects increase the susceptibility of tumor cells to cell death. Several studies have reported that proteins or genes such as RBL1 [ 55 ], p53 [ 56 ], Rad51 [ 57 ], and BRCA2 [ 58 ] are involved in DNA repair. Mutations or loss of function of these proteins or genes have been implicated in cancer, and RT + HT has shown an inhibitory effect on cancer proliferation by regulating these factors.…”

Implantable smart hyperthermia nanofibers for cancer therapy: Challenges and opportunities

“…The recognized biological effects of heat stress include the inhibition of DNA damage repair through protein inactivation or denaturation, raised drug delivery owing to heat‐induced upsurges in blood flow and vascular permeability, and augmented cellular uptake (Singh et al, 2020). A rise in the direct cytotoxicity of the drug have all been linked to this enhanced response in which antitumor agents are potentiated by hyperthermia leading to overwhelming drug resistance (Ni et al, 2022; Salvador et al, 2021). The technique produces thermal energy by subjecting magnetic NPs to an alternating magnetic field.…”

Is there a role for hyperthermic intraperitoneal chemotherapy in ovarian cancer?

“…Despite the exact mechanism being unknown, hyperthermia has been shown to cause lethal cell damage [18 ▪▪ ,19 ▪ ,20 ▪ ,21,22]. Using mass spectrometry-based quantitative proteomics to analyze the effects of thermochemotherapy on an ovarian cancer cell line, Ni et al [18 ▪▪ ] showed that ‘hyperthermia mainly affected the DNA damage repair process in heat-sensitive ovarian cancer cells, which enhanced their sensitivity to chemotherapeutic drugs’.…”

“…Despite the exact mechanism being unknown, hyperthermia has been shown to cause lethal cell damage [18 ▪▪ ,19 ▪ ,20 ▪ ,21,22]. Using mass spectrometry-based quantitative proteomics to analyze the effects of thermochemotherapy on an ovarian cancer cell line, Ni et al [18 ▪▪ ] showed that ‘hyperthermia mainly affected the DNA damage repair process in heat-sensitive ovarian cancer cells, which enhanced their sensitivity to chemotherapeutic drugs’. Moukarzel et al [19 ▪ ] obtained normal and tumor samples pre and post-HIPEC treatment with carboplatin in patients with recurrent ovarian cancer and performed RNA sequencing to elucidate the effect of HIPEC on tumor cells.…”