Harnessing the synergy of nanosecond high-power microwave pulses and cisplatin to increase the induction of apoptosis in cancer cells through the activation of ATR/ATM and intrinsic pathways.

The therapeutic application and dose of cisplatin are limited due to its toxicity to normal cells. Therefore, combination treatments might be the solution with a low dose of cisplatin. The combination effect of nanosecond pulsed high-power microwave (HPM) with cisplatin has not been investigated before. In this work, we aimed to investigate and assess the potential synergistic effects and most likely underlying mechanisms resulting from the combination of nanosecond pulsed HPM and cisplatin. Three cancer (SKOV3, H460, and MDA-MB231) and two normal (MRC5 and HGF) cell lines underwent separate treatments with HPM and cisplatin, as well as a combined treatment. A higher reduction of viability was observed in cancer cells using combination treatments following 24-h incubation. Cell death, membrane permeability, and intracellular reactive oxygen species (ROS) levels exhibit a noteworthy increase in response to combined 60 pulses of HPM (HPM60) and cisplatin (0.5 μM) treatments compared to control and individual treatments. Elevated γ-H2AX levels indicate DNA double-strand breaks in combined treatments. Additionally, upregulation of ATR/ATM, Chk1/Chk2, P53, and caspase 3/8, Bax, PARP, and Bcl2 confirms DNA damage and mitochondrial dysfunction, leading to apoptosis. Remarkably, half maximal inhibitory concentration (IC) results showed that HPM60 and cisplatin (0.5 μM) resulted in 16 times higher cell death in SKOV3 and H460 cells compared to cisplatin alone. Moreover, the efficacy of this combined treatment led to an over 50 % decrease in the viability of cancer cells. On the other hand, normal cells (MRC5 and HGF) exhibited only a minor 3-5 % decrease in viability under the same treatment conditions. The obtained results elucidate the cellular mechanisms driving cell apoptosis/death, offering insights for potential advancements in cancer therapy through the combined application of nanosecond pulses of HPM and cisplatin. This serves as a first step for future investigations in this domain.