Combination of cycling hyperthermia and echinacoside creates a synergistic curing effect on pancreatic cancer PANC-1 cells.
Therapy targeting the suppression of human MutT homolog 1 (MTH1) has been gaining ground in recent years, thanks to its resulting significant increase of 8-hydroxy-2'-deoxyguanosine triphosphate (8-oxo-dGTP) accumulation in genomic DNA, causing DNA damage and apoptotic cell death. Echinacoside (Ech), a natural phenylethanoid glycoside first extracted from Echinacea angustifolia or desert plant Cistanches, is one of a few natural products that are capable of inhibiting the MTH1 function. It, however, is difficult to apply it in clinical trials, due to high cost for effective dosage in need. In this study, we show that the integration of Ech with thermal cycling-hyperthermia (TC-HT), a novel physical treatment, significantly augments its anticancer efficacy while simultaneously decreasing the necessary dosage. Specifically, 20 μM Ech with TC-HT reduced human pancreatic carcinoma cell line PANC-1 viability to 29.6% of the control, comparable to 28.7% of the control by 100 μM Ech alone. The combined treatment reduced MTH1 expression to 0.42-fold, initiating oxidative damage and apoptosis. Notably, 8-oxo-dGTP increased to 3.67-fold of the control, indicating enhanced oxidative DNA damage and 31.8% apoptosis. This oxidative stress further influenced critical signaling pathways, as p-ERK and p-JNK shifted to 0.59- and 5.55-fold, respectively, indicating a switch from survival to apoptotic signaling. Concurrently, mitochondrial apoptotic markers Bax/Bcl-2 and cleaved poly (ADP-ribose) polymerase increased to 4.22- and 7.12-fold, respectively. These results indicate that its effect is expected to be comparable to the treatment strategy containing MTH1, Bcl-2, and extracellular signal-regulated kinase inhibitors, posing as new promising approach in cancer treatment.