Study on the effect of a triple cancer treatment of propolis, thermal cycling-hyperthermia, and low-intensity ultrasound on PANC-1 cells.

To reduce side effects and enhance treatment efficacy, study on combination therapy for pancreatic cancer, a deadly cancer, has gained much attraction in recent years. In this study, we propose a novel triple treatment combining propolis and two physical stimuli-thermal cycling-hyperthermia (TC-HT) and low-intensity ultrasound (US). The study found that, after the triple treatment, the cell viability of a human cancer cell line PANC-1 decreased to a level 80% less than the control, without affecting the normal pancreatic cells. Another result was excessive accumulation of reactive oxygen species (ROS) after the triple treatment, leading to the amplification of apoptotic pathway through the MAPK family and mitochondrial dysfunction. This study, to the best of our knowledge, is the first attempt to combine TC-HT, US, and a natural compound in cancer treatment. The combination of TC-HT and US also promotes the anticancer effect of the heat-sensitive chemotherapy drug cisplatin on PANC-1 cells. It is expected that optimized parameters for different agents and different types of cancer will expand the methodology on oncological therapy in a safe manner.

Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and ß-amyloid-induced cell injury through stress response mechanisms involving Akt pathway.

Neurodegenerative diseases (NDDs) are becoming a major threat to public health, according to the World Health Organization (WHO). The most common form of NDDs is Alzheimer's disease (AD), boasting 60-70% share. Although some debates still exist, excessive aggregation of ß-amyloid protein (Aß) and neurofibrillary tangles has been deemed one of the major causes for the pathogenesis of AD. A growing number of evidences from studies, however, have suggested that reactive oxygen species (ROS) also play a key role in the onset and progression of AD. Although scientists have had some understanding of the pathogenesis of AD, the disease still cannot be cured, with existing treatment only capable of providing a temporary relief at best, partly due to the obstacle of blood-brain barrier (BBB). The study was aimed to ascertain the neuroprotective effect of thermal cycle hyperthermia (TC-HT) against hydrogen peroxide (H2O2) and Aß-induced cytotoxicity in SH-SY5Y cells. Treating cells with this physical stimulation beforehand significantly improved the cell viability and decreased the ROS content. The underlying mechanisms may be due to the activation of Akt pathway and the downstream antioxidant and prosurvival proteins. The findings manifest significant potential of TC-HT in neuroprotection, via inhibition of oxidative stress and cell apoptosis. It is believed that coupled with the use of drugs or natural compounds, this methodology can be even more effective in treating NDDs.

Application of non-invasive low-intensity pulsed electric field with thermal cycling-hyperthermia for synergistically enhanced anticancer effect of chlorogenic acid on PANC-1 cells.

Most existing cancer treatments involve high-cost chemotherapy and radiotherapy, with major side effects, prompting effort to develop alternative treatment modalities. It was reported that the combination of thermal-cycling hyperthermia (TC-HT) and phenolic compound exhibited a moderate cytotoxic effect against human pancreatic cancer PANC-1 cells. In this study, we investigate the efficacy of triple combination in PANC-1 cancer cells by adopting low-intensity pulsed electric field (LIPEF) to couple with TC-HT and CGA (chlorogenic acid). The study finds that this triple combination can significantly impede the proliferation of PANC-1 cells, with only about 20% viable cells left after 24h, whereas being non-toxic to normal cells. The synergistic activity against the PANC-1 cells was achieved by inducing G2/M phase arrest and apoptosis, which were associated with up-regulation of p53 and coupled with increased expression of downstream proteins p21 and Bax. Further mechanism investigations revealed that the cytotoxic activity could be related to mitochondrial apoptosis, characterized by the reduced level of Bcl-2, mitochondrial dysfunction, and sequential activation of caspase-9 and PARP. Also, we found that the triple treatment led to the increase of intracellular reactive oxygen species (ROS) production. Notably, the triple treatment-induced cytotoxic effects and the elevated expression of p53 and p21 proteins as well as the increased Bax/Bcl-2 ratio, all could be alleviated by the ROS scavenger, N-acetyl-cysteine (NAC). These findings indicate that the combination of CGA, TC-HT, and LIPEF may be a promising modality for cancer treatment, as it can induce p53-dependent cell cycle arrest and apoptosis through accumulation of ROS in PANC-1 cells.

Thermal cycling as a novel thermal therapy to synergistically enhance the anticancer effect of propolis on PANC­1 cells.

Hyperthermia (HT) has shown potential in cancer therapy. In particular, it appears to sensitize cancer cells to chemotherapy. However, a major concern associated with HT is that the thermal dosage applied to the tumor cells may also harm the normal tissue cells. Besides, the drugs used in HT are conventional chemotherapy drugs, which may cause serious side effects. The present study demonstrated a novel methodology in HT therapy called thermal cycle (TC)­HT. With this strategy, a therapeutic window with a maximum synergistic effect was created by combining TC­HT with natural compounds, with minimal unwanted cell damage. The natural compound propolis was selected, and the synergistic anticancer effect of TC­HT and propolis was investigated in pancreatic cancer cells. The present results demonstrated for the first time that TC­HT could enhance the anticancer effect of propolis on PANC­1 cancer cells through the mitochondria­dependent apoptosis pathway and cell cycle arrest. Combined treatment greatly suppressed mitochondrial membrane potential, which is an important indicator of damaged and dysfunctional mitochondria. Furthermore, the cell cycle­regulating protein cell division cycle protein 2 was downregulated upon combined treatment, which prevented cellular progression into mitosis. The present study offers the first report, to the best of our knowledge, on the combination of TC­HT with a natural compound for pancreatic cancer treatment. It is anticipated that this methodology may be a starting point for more sophisticated cancer treatments and may thereby improve the quality of life of many patients with cancer.

Thermal cycling-hyperthermia in combination with polyphenols, epigallocatechin gallate and chlorogenic acid, exerts synergistic anticancer effect against human pancreatic cancer PANC-1 cells.

Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment.

The protective effect of non-invasive low intensity pulsed electric field and fucoidan in preventing oxidative stress-induced motor neuron death via ROCK/Akt pathway.

With the expansion of the aged population, it is predicted that neurodegenerative diseases (NDDs) will become a major threat to public health worldwide. However, existing therapies can control the symptoms of the diseases at best, rather than offering a fundamental cure. As for the complex pathogenesis, clinical and preclinical researches have indicated that oxidative stress, a central role in neuronal degeneration, is a possible therapeutic target in the development of novel remedies. In this study, the motor neuron-like cell line NSC-34 was employed as an experimental model in probing the effects induced by the combination of non-invasive low intensity pulsed electric field (LIPEF) and fucoidan on the H2O2-induced neuron damage. It was found that single treatment of the LIPEF could protect the NSC-34 cells from oxidative stress, and the protective effect was enhanced by combining the LIPEF and fucoidan. Notably, it was observed that single treatment of the LIPEF obviously suppressed the H2O2-enhanced expression of ROCK protein and increased the phosphorylation of Akt in the H2O2-treated NSC-34 cells. Moreover, the LIPEF can be easily modified to concentrate on a specific area. Accordingly, this technique can be used as an advanced remedy for ROCK inhibition without the drawback of drug metabolism. Therefore, we suggest the LIPEF would be a promising strategy as a treatment for motor neurodegeneration and warrant further probe into its potential in treating other neuronal degenerations.