Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy

Abstract

Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies.

5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy

“…We suggest that combination treatment with 5-FU and TTFields impaired CRC cell proliferation, survival, cell invasion, and migration while promoting apoptosis and autophagic cell death. We hope that our observations provide important new insight and experimental evidence supporting the use of multimodal treatment of CRC with TTFields + 5-FU combination therapy as previously reported in with TTFields + sorafenib combination therapy [14].…”

“…After 5-FU exposure, TTFields was applied to the cells, which were then incubated for a further 48 h. The apoptotic cells were evaluated by using an Annexin V-FITC/PI apoptosis detection kit (BD Biosciences, San Jose, CA, USA) according to the manufacturer's protocol [19] 4.9. Western Blotting After 5-FU treatment, the colon cancer cells were exposed to TTFields, which were then incubated for 24 or 48 h. The cells were then lysed with RIPA buffer; proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes according to the manufacturer's protocol [14]…”

“…Invasion and migration abilities were measured in vitro using Transwell chambers, as described previously [14] 4. 16…”

Barium Titanate Nanoparticles Sensitise Treatment-Resistant Breast Cancer Cells to the Antitumor Action of Tumour-Treating Fields

“…Although there is an accumulating body of evidence demonstrating enhanced efficacy of the combined treatment of TTFields and chemotherapeutic agents or radiotherapy 1,2,9,[11][12][13][14][15][16][17][18]29 , not much is known about TTFields-responsive sensitisers. Here, we report novel TTFields-responsive sensitisers, BTNPs, characterised by high dielectric constants.…”

“…Early clinical trials have shown that only TTFields treatment for GBM patients was not significantly better than conventional chemotherapy 3,9,[11][12][13] . However, recent preclinical studies suggest that combination therapy of TTFields with conventional treatments including chemotherapy, immunotherapy, and radiotherapy are more effective than TTFields monotherapy in GBM 1,2,9,[11][12][13][14][15][16][17][18] . Despite the promise shown by TTFields as a viable cancer therapy, not much is known about TTFields responsive sensitiser.…”