Low-frequency magnetic field therapy for glioblastoma: Current advances, mechanisms, challenges and future perspectives

Abstract

Background: Glioblastoma (GBM) is the most common malignant tumour of the central nervous system. Despite recent advances in multimodal GBM therapy incorporating surgery, radiotherapy, systemic therapy (chemotherapy, targeted therapy), and supportive care, the overall survival (OS) remains poor, and long-term survival is rare. Currently, the primary obstacles hindering the effectiveness of GBM treatment are still the blood-brain barrier and tumor heterogeneity. In light of its substantial advantages over conventional therapies, such as strong penetrative ability and minimal side effects, low-frequency magnetic fields (LF-MFs) therapy has gradually caught the attention of scientists.

Aim of review: In this review, we shed the light on the current status of applying LF-MFs in the treatment of GBM. We specifically emphasize our current understanding of the mechanisms by which LF-MFs mediate anticancer effects and the challenges faced by LF-MFs in treating GBM cells. Furthermore, we discuss the prospective applications of magnetic field therapy in the future treatment of GBM. Key scientific concepts of review: The review explores the current progress on the use of LF-MFs in the treatment of GBM with a special focus on the potential underlying mechanisms of LF-MFs in anticancer effects. Additionally, we also discussed the complex magnetic field features and biological characteristics related to magnetic bioeffects. Finally, we proposed a promising magnetic field treatment strategy for future applications in GBM therapy.

Keywords: Antitumour; Glioblastoma; Low-frequency magnetic fields; Molecular mechanism.

Graphical abstract

Fig. 1

Historical timeline of the emergence of MFs as novel therapy for tumour patients. In 1961 and 1971, two papers demonstrating the anticancer effects of MFs in vitro and in vivo were published. Following the promising preclinical data, a number of clinical trials investigating the safety and efficacy of MFs for the treatment of malignant tumours, including GBM, were completed (details described at each relevant date), and MF therapy is expected to be approved for the treatment of recurrent and newly diagnosed GBM in the future.

Fig. 2

Flow diagram of the study selection process.

Fig. 3

Possible mechanisms of Ca2 + influx induced by LF-MFs. 1. LF-MFs may induce Ca2 + influx into the cell through ion channel proteins (e.g., TRPV1, VGCC, or TRPM8) in the cell membrane or through AMPAR or by promoting membrane permeability and membrane perforation, and the increase in the intracellular calcium concentration activates endoplasmic reticulum and/or mitochondrial apoptosis pathways to induce apoptosis and the CAMKII-p38 MAPK pathway and decreases HMGA2 expression through CAMKII-mediated β-catenin degradation to block the growth of cancer cells as well as CSCs; furthermore, the change suppresses angiogenesis in the tumour microenvironment by suppressing β-catenin-miR-1246 signalling. 2. Calcium can promote cell differentiation by activating p53 and Notch signalling, and overexpression of SOD induced by ROS increases cell differentiation.

Fig. 4

Regulation of cell cycle checkpoints（G1/S and G2/M）and apoptosis by protein 38-mitogen activated protein kinases (P38-MAPKs) and LF-MFs. 1. LF-MFs activate the p38 pathway: MFs activate P38-MAPKs by inducing DNA damage and p38 activates MAPKAP-K2/3 (MK2/3). Both p38 and MK2/3 can regulate the G1/S and G2/M cell cycle transitions by phosphorylating and inhibiting the CDK-activating phosphatase, CDC25. 2. p38 regulates the G1/S cell cycle transition: Cyclin D binds and activates CDK4 and/or CDK6 in response to growth factor. In late G1, cyclin E binds and activates CDK2, and G1 CDKs hyperphosphorylate Rb, a major tumour suppressor and cell cycle inhibitor, which binds and inhibits E2F transcription factors on chromatin to induce E2F release and subsequent S phase gene activation. CDKs are controlled by CDK inhibitor proteins including the CIP/KIP family (p21, p27, p57) that inhibits CDK2 and the INK4 family (p15, p16, p18, p19) that inhibits CDK4 and CDK6, whereas p19 activates this pathway by activating p21 through p53. Both p19 and p53 are activated by p38. p38 also mediates G1 arrest via phosphorylation of cyclin D, resulting in its degradation, and p38 phosphorylates Rb at different sites, thereby enhancing E2F inhibition. 3. p38 regulates the G2/M cell cycle transition: During G2, phospho-CDK1 is inactive, and cyclin B/CDK1 activated dephosphorylation of CDK1 through CDC25, controlling the transition from G2 phase into mitosis. 4. p38 regulates the BCL2 family: In the context of DNA damage, active p38 upregulates the expression of BH3-only proteins (BIM, BID, PUMA, etc.), and the apoptotic effectors (BAK and BAX) from pores in the outer mitochondrial membrane resulting in cytochrome c release, caspase activation, and cell death. Active p38 phosphorylates several anti-apoptotic BCL2 proteins (BCL2, MCL1, and BCLxL), resulting in their ubiquitination and degradation, which leads to cell death. The BCL2 family also regulates the cell cycle; for example, BCL2 inhibits p27, and MCL1 inhibits CDK4/6 by inhibiting P18. However, phosphorylated Rb binds and inhibits BAX until Rb is dephosphorylated. 5. p38 regulates the cell cycle and apoptosis through p53: P53 activated by p38 inhibits CDK2 though activating p21 and increases the expression of apoptotic effectors (BAK and BAX), which activates a pathway upstream of caspase activation to induce apoptosis. p53 can also induce the synthesis of GADD45, which can bind PCNA and inhibit DNA synthesis, thus inhibiting cells from entering S phase.

Fig. 5

Possible mechanismsof LF-MFs on apoptosis of GBM. LF-MFs may trigger apoptotic cell death by increasing the p53 level, decreasing ERK phosphorylation, or inhibiting PI3K/AKT signalling pathway; they may also function through the mitochondrial-dependent pathway.

Fig. 6

Possible mechanisms by which LF-MFs affect GBM cell ferroptosis. LF-MFs can reduce the phosphorylation of ERK in GBM to regulate ferroptosis. The increased expression level of p53 induced by LF-MFs mediates ferroptosis of GBM cells through SLC7A11 transcription inhibition or direct binding of p53 with DPP4 to inhibit NOX.

Fig. 7

Hypothesis on the mechanisms underlying the effects of LF-MFs on GBM cells. A. On the one hand, MFs can not only cause the opening of ion channels, such as voltage-gated Ca²⁺ channels (VGCCs) or mechanosensitive ion channels, but also generate Lorentz forces on moving charged particles, ultimately inducing ion influx, for example, MFs contributes to inducing cancer cell apoptosis by mediating the influx of Ca²⁺ through the mitochondrial pathway, and mitochondrial energy metabolism can produce paired free radicals or ion free radicals, MFs can inhibit or catalyse biochemical reactions by interfering with the conversion of radical pairs from the singlet state to the triplet state; On the other hand, MFs transmit the signals into cells by influencing the signal transduction mediated by cell receptors, thereby affecting biological effects. B. MFs can affect the arrangement of tubulin and DNA, thus interfere with mitosis and induce tumor cell death. C.The resonance effect occurs when the frequency of biochemical reaction mechanism is the same as that of magnetic field signal, and then shows significant biological effect.