Enhancing therapeutic efficacy in triple‐negative breast cancer and melanoma: synergistic effects of modulated electro‐hyperthermia (mEHT) with NSAIDs especially COX‐2 inhibition in in vivo models

Abstract

Triple‐negative breast cancer (TNBC) is a leading cause of cancer mortality and lacks modern therapy options. Modulated electro‐hyperthermia (mEHT) is an adjuvant therapy with demonstrated clinical efficacy for the treatment of various cancer types. In this study, we report that mEHT monotherapy stimulated interleukin‐1 beta (IL‐1β) and interleukin‐6 (IL‐6) expression, and consequently cyclooxygenase 2 (COX‐2), which may favor a cancer‐promoting tumor microenvironment. Thus, we combined mEHT with nonsteroid anti‐inflammatory drugs (NSAIDs): a nonselective aspirin, or the selective COX‐2 inhibitor SC236, in vivo. We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. Moreover, the strongest tumor destruction ratio was observed in the combination SC236 + mEHT groups. Tumor damage was accompanied by a significant increase in cleaved caspase‐3, suggesting that apoptosis played an important role. IL‐1β and COX‐2 expression were significantly reduced by the combination therapies. In addition, a custom‐made nanostring panel demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs. In conclusion, mEHT combined with a selective COX‐2 inhibitor may offer a new therapeutic option in TNBC.

Protective effect of synbiotic combination of Lactobacillus plantarum SC-5 and olive oil extract tyrosol in a murine model of ulcerative colitis

“…Although anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the production of inflammatory mediators, helping to control the development of ulcerative colitis and alleviate symptoms [ 9 ]. However, the long-term use of antibiotics, aminosalicylates, corticosteroids, and immunosuppressants may lead to a series of adverse reactions, such as allergic reactions, metabolic disorders, and liver diseases [ 10 ]. These adverse reactions may have an impact on the health of patients.…”

Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model

“…25−28 mEHT uses an amplitude-modulated, 13.56 MHz radiofrequency electromagnetic field by capacitive coupling between two electrodes surrounding the cancer. 29,30 Due to the difference in bioelectrical properties between cancerous and healthy tissues, 31,32 the electromagnetic field energy is absorbed mainly by cancer tissues, resulting in cancer-specific tissue damage. 33,34 At the cellular level, mEHT generates heat, leading to cellular stress and upregulation of HSPs.…”

“…Modulated electro-hyperthermia (mEHT) is a noninvasive adjuvant cancer treatment approved for clinical use in different cancer types. − mEHT uses an amplitude-modulated, 13.56 MHz radiofrequency electromagnetic field by capacitive coupling between two electrodes surrounding the cancer. , Due to the difference in bioelectrical properties between cancerous and healthy tissues, , the electromagnetic field energy is absorbed mainly by cancer tissues, resulting in cancer-specific tissue damage. , At the cellular level, mEHT generates heat, leading to cellular stress and upregulation of HSPs . We previously demonstrated enhanced anticancer effects of mEHT by inhibiting HSP70 in vitro and heat shock factor 1 (HSF1) in vivo, utilizing the small molecule inhibitors of the heat shock response central regulator (i.e., HSF1): quercetin and KRIBB11, and by knocking down HSF1 production of the tumor cells with a CRISPR/Cas9 construct .…”