Molecular mechanism of tumor electric field therapy

Tumor electric field therapy (tumor field fields, TTFields) is a non-invasive physical model for tumor therapy, low-intensity, medium-frequency AC electric field in the induced DNA double-stranded fracture (DSBs) at the same time, weakens the re-engagement of DSBs; The FDA has approved TTFields in combination with tamoxamine to treat recurrence and newly diagnosed glioblastoma (GBM)Karanam NK, of the Oncology Department at the University of Texas Southwestern Medical Center, and others studying the biological mechanismof of TTFields' combination of tamoxamine treatment syrapy for GBM, published in the March 2020 issue of Translational Researchfindingsfindings that TTFields has a synergy with a variety of chemotherapy drugs to treat tumors, tTFields not only delays the filament of tumor cells, but also kills tumor cells through a variety of other mechanismsTTFields reduces the speed of replication fork movement and triggers DNA replication resistance: THE MCM10 and MCM6 genes in tumor cells are critical for the start and extension of DNA replication, TTFields inhibits MCM10 and MCM6 gene expression, suggests that TTFields can lead to DNA replication resistance, shorten the length of newly synthesized DNA, and significantly shorten the length of newly synthesized DNA as TTFields processing time increasesCompared to the control group, TTFields treatment for 30, 45, and 60 hours resulted in a significant reduction in DNA length in H157 and 22%, 34%, and 47% of NSCLC cell lines in H1299, respectively (Figure 1)Figure 1TTFields inhibits the expression of the MCM10 and MCM6 genes and the replication fork movement speed (replica fork speed)AStandardized LEVELS OF MCM10 AND MCM6 gene expressionThe hetogram of DNA length changes in B, C.NSCLC cell lines H157 and H1299DBox chart shows the DNA length range in NSCLC cell lines H157 and H1299 at each point in timeTTFields promoteR ring formation: H157 is more sensitive to TTFields treatment than NSCLC cell line H1299, H157, and the increase in The R ring in H157 is more pronounced as TTFields processing time increasesIn addition, immunofluorescent staining also found a significant increase in TTFields in the R ring in H157 and H1299 (Figure 2)Figure 2TTFields promotes the formation of the R ring A The effect of TTFields processing time on the formation of the R ring was analyzed by the spot marking method and B immunofluorescent staining quantitatively TTFields pretreatment enhances the tumor-killing effect of radiotherapy: TTCLC field pretreatment enhances the sensitivity of NSCLC cell lines to radiotherapy (Figure 3) Compared to single radiotherapy, TTField pretreatment enhances the tumor-killing effect of radiotherapy In addition, adjusting the TTField treatment sequence can also work together to enhance the radiotherapy tumor effect Figure 3 TTFields pretreatment enhances the effect of radiotherapy A.NSCLC cell lines H157 and H1299 programme synergy index (CI) after TTFields pre-treatment of post-treatment radiotherapy; TTFields Enhances Tumor Cell Sensitivity to CIS: TTFields worked with cisplatin to enhance the sensitivity of NSCLC cell lines to cisplatin and enhance the tumor-killing effect (Figure 4) Figure 4 TTFields enhances the sensitivity of NSCLC cell lines to cisplatin TTFields works with cisplatin to increase the tumor-killing effect TTFields enhances the cytotoxicity of PARP1 inhibitors: TTFields combined with PARP1 inhibitor Olapani to produce synergistic effects on tumor cells when given or not given radiation, suggesting that TTFields can increase the sensitivity of tumor cells to a variety of damaged DNA or interfere with replication fork drugs (Figure 5) In addition, TTFields, Olapani and radiotherapy can be used to further improve the CI value Figure 5 TTFields enhances cytotoxicity of PARP1 inhibitors; Co-using TTFields and Olapani or radiotherapy can co-inhibit the proliferation of NSCLC cell lines H157 and H1299, further improving the CI value TTFields caused DNA replication resistance and interference to divide fission: in multiple NSCLC cell lines, TTFields inhibited the expression of 33 genes associated with filament division in regulated cells; Real-time fluorescence quantitative reverse polymerase chain reaction found that TTFields inhibited the expression of KIF11, CENPE, WEE1 and SNRNP200 genes in NSCLC cell lines H157 and H1299, indicating that TTFields can simultaneously trigger DNA replication resistance and interfere with filament division (Figure 6) Figure 6 TTFields inhibits the regulation of cell filament division and enhances DNA replication resistance to key gene expression A TTFields inhibits the expression of 33 key genes that have filamentdivision with regulated cells B, C Real-time fluorescence quantitative reverse transcription polymerase chain reaction found that TTFields inhibited the expression of KIF11, CENPE, WEE1 and SNRNP200 genes in NSCLC cell lines H157 and H1299 TTFields' main mechanism of action: TTFields causes cell death by interfering with cell stent protein positioning, destroying spindle formation, inhibiting cell division and chromosomal separation, and eventually causing cell death (Figure 7) TTFields inhibits the expression of FA pathway genes, which are involved in DNA damage repair and maintain replication fork stability TTFields increases DNA replication resistance and inhibits FA pathway gene expression can cause DNA damage In addition, tTFields increases DNA replication resistance and further reduces the ability to react to DNA damage repair, resulting in slower replication fork movement, replication errors, R ring formation, genomic instability, and cell death In the cell cycle checkpoint regulation mechanism, TTFields interferes with filament division in phase M, causing RESISTANCE to DNA replication in phase S, which simultaneously causes cell death Figure 7 TTFields is the main mechanism of action conclusions
the study shows that the environmental effects of TTFields can be used to develop a variety of strategies to improve the effectiveness of tumor treatment It is recommended that TTFields can be used before or at the same time as split radiotherapy or chemotherapy, causing DNA damage or strengthening resistance to tumor DNA replication.