Hyperthermia as a Potential Cornerstone of Effective Multimodality Treatment with Radiotherapy, Cisplatin and PARP Inhibitor in IDH1-Mutated Cancer Cells

Abstract

Mutations in the isocitrate dehydrogenase 1 (IDH1MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and > 80% of low-grade gliomas. IDH1MUT are causal in the development and progression of these types of cancer due to neomorphic production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Intracellular accumulation of D-2HG has been implicated in suppressing homologous recombination and renders IDH1MUT cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5′-diphosphate–ribose) polymerase inhibitors (PARPi). Hyperthermia increases the efficacy of DNA-damaging therapies such as radiotherapy and platinum-based chemotherapy, mainly by inhibition of DNA repair. In the current study, we investigated the additional effects of hyperthermia (42 °C for 1 h) in the treatment of IDH1MUT HCT116 colon cancer cells and hyperthermia1080 chondrosarcoma cancer cells in combination with radiation, cisplatin and/or a PARPi on clonogenic cell survival, cell cycle distribution and the induction and repair of DNA double-strand breaks. We found that hyperthermia in combination with radiation or cisplatin induces an increase in double-strand breaks and cell death, up to 10-fold in IDH1MUT cancer cells compared to IDH1 wild-type cells. This vulnerability was abolished by the IDH1MUT inhibitor AGI-5198 and was further increased by the PARPi. In conclusion, our study shows that IDH1MUT cancer cells are sensitized to hyperthermia in combination with irradiation or cisplatin and a PARPi. Therefore, hyperthermia may be an efficacious sensitizer to cytotoxic therapies in tumors where the clinical application of hyperthermia is feasible, such as IDH1MUT chondrosarcoma of the extremities.

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

“…One study addressed the dissociation and reformation of Rad51 proteins as crucial in radiosensitization by HT [ 62 ], while another reported chromosomal abnormalities and transient BRCA2 degradation [ 63 ]. Another study found that mutations in IDH1 lead to the accumulation of the oncometabolite D -2HG, which suppresses homologous recombination repair and lowers NADPH [ 67 ]. According to a study in 2016, inhibition of DSB repair promotes cell cytotoxicity, cell cycle arrest, and Caspase-3 activation [ 64 ].…”

“…Khurshed et al demonstrated that the addition of HT (42 °C, 60 min) enhanced the efficiency of multimodal therapy with RT, cisplatin, and PARPi in IDH1 MUT , IDH1 WT HCT116 colon cancer cells, and Hyperthermia1080 chondrosarcoma cancer cells [ 67 ]. Isocitrate dehydrogenase 1 (IDH1) is a homodimeric enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (αKG) via the reduction of NADP+ to NADPH.…”

D-α-tocopherol polyethylene glycol (1000) succinatecontaining microemulsion enhances the anticancer effect of cisplatin in human lung epidermoid carcinoma cells

“…Cancer has become a major global health concern in the past several decades. Main treatment options for cancer therapy are surgical dissection for removal of the tumor tissue [1], chemo-and radio-therapy [2], hyperthermia [3] and hormone therapy [4] that contribute to the killing and suppressing the invasiveness of cancer cells. Surgical resection is the main treatment for most of the cases but it has the potential to trigger metastasis [1].…”