Cancer Cell Permeability Induced by Tumor Treating Fields (TTFields) as a Physical Approach to Improve Chemotherapy Uptake and Overcome Multidrug Resistance

Abstract

Multidrug resistance (MDR) is a major challenge in cancer treatment. One predominant MDR mechanism involves the overexpression of ATP-binding cassette transporter proteins on the cell membrane, leading to increased chemotherapy efflux. Strategies to resolve MDR have not yet yielded substantial survival benefits. Tumor Treating Fields (TTField) represent an innovative therapeutic modality for cancer treatment and have been shown to enhance membrane permeability in glioblastoma cells. The current study aimed to characterize this phenomenon and evaluate its potential to increase chemotherapy accumulation, thus overcoming MDR. In vitro analyses using the exclusion dye 7-aminoactinomycin D demonstrated that TTFields-induced enhancement of membrane permeability is pan-cancer while specific to cancer cells, reversible, and requires cell-cycle progression through the G2–M phase. Furthermore, TTFields significantly increased intracellular accumulation of doxorubicin (DOX), mitoxantrone, and cisplatin in resistant cells, restoring uptake to levels observed in sensitive cells, without altering MDR transporter expression. Increased chemotherapy accumulation was confirmed in vivo as demonstrated by elevated DOX accumulation in breast tumors and increased paclitaxel accumulation in lung tumors. Importantly, TTFields sensitized both DOX-sensitive and DOX-resistant cells to DOX-induced cytotoxicity in vitro. In mouse models bearing breast tumors, co-administration of therapeutic or sub-therapeutic DOX doses together with TTFields significantly reduced tumor growth compared with either treatment alone. In conclusion, the findings suggest that adding TTFields to chemotherapy regimens may enhance drug delivery and efficacy in tumors exhibiting MDR. Further clinical studies evaluating TTFields concomitant with chemotherapy in patients with MDR cancer are warranted.