Hyperthermia Suppresses Post - In Vitro Proliferation and Tumor Growth in Murine Malignant Melanoma and Colon Carcinoma

Abstract

Background: Several studies have highlighted hyperthermia's ability to enhance the effectiveness of radiation and chemotherapy in various in vitro and in vivo cancer models. Materials and Methods: In vivo murine models of malignant melanoma and colon carcinoma were utilized for demonstrating hyperthermia's therapeutic effectiveness by examining levels of caspase 3, COX-2 and phospho-H2A.X (Ser139) as endpoints of apoptosis, proliferation and DNA damage respectively. Results: Hyperthermia induced in vitro cytotoxicity in malignant melanoma (B16-F10) and colon carcinoma (CT26) cell lines. In addition, it reduced post-in vitro proliferation and suppression of tumor growth by inducing the expression of caspase-3 and phospho-H2A.X (Ser139) while reducing the expression of COX-2 in both murine cancer models. Conclusion: Hyperthermia can exert therapeutic effectiveness against melanoma and colon carcinoma by inhibiting a number of critical cellular cascades including apoptosis, proliferation and DNA damage. One of the most aggressive and deadliest malignancies of all solid tumors is malignant melanoma (MM). Its incidence rates have been continuously rising worldwide while the disease accounts for the majority of skin cancer-related deaths (1-4). MM occurs from the accumulation of genetic and metabolic abnormalities of melanocytes as well as other contributing factors like numerous atypical nevi (i.e. benign proliferations of melanocytes), genetic predisposition and solar ultraviolet (UV) (5-7). In particular, evidence from various studies have linked exposure to UV radiation with the increased occurrence of the disease, due to the mutagenic properties of UVR, thus making it the leading risk factor (8-10). The majority of MM cases present an active BRAF mutation, with V 600E being the most common one accounting for 90% of cases. The activation of other oncogene pathways including RAS, c-KIT, NRAS, PI3K and PTEN as well as inactivation of tumor suppressors such as CDKN2A have been also associated with the development of the disease (11, 12). However, although there has been significant progress on understanding MM's biology, the disease's pathogenesis has yet to be well characterized. Although there is remarkable progress in developing more targeted therapeutic approaches there is still a great need to design more effective treatment strategies due to the poor responsiveness of MM to current therapeutic means (13-15). On the other hand, colorectal or colon carcinoma (CRC) is a tumor type originating from epithelial cells residing in the colon or rectum of the gastrointestinal tract (16, 17). CRC is the third most common type of cancer diagnosed globally while it is the fourth leading cause of cancer-related 2307 This article is freely accessible online.

Ultrasound microbubble potentiated enhancement of hyperthermia-effect in tumours

“…That study correlated changes in tumour size with an expression of protein levels that stimulate apoptotic pathways. Data indicated HT-treated groups expressed increased levels of active caspase-3 and phospho-H2A.X (Ser139) and reduced levels of COX-2 compared to the control group [51]. Similarly, exposure of cells and tumours with USMB in vivo and in vitro have demonstrated enhanced tumour inhibition via regulation of Bax and Bcl-2 [52] along with increased expression of cell-death related caspase-3, cleaved caspase-3, and caspase-8 [53].…”

An Evaluation of the Anti-Carcinogenic Response of Major Isothiocyanates in Non-Metastatic and Metastatic Melanoma Cells

“…MM arises from the progressive accumulation of melanocytic lesions while important risk factors include genetic predisposition as well as prolonged UV exposure, strongly associated with the onset and progression of the disease [8][9][10]. A number of genetic abnormalities have been identified and associated with the onset of MM including mutations in BRAF, NRAS and KIT while additional mutations in TP53, TERT and PTEN are required for the occurrence of the invasiveness of the disease [11][12][13][14]. Currently, treatment options for early stages of MM include surgical resection while systemic therapy (i.e., chemotherapy (e.g., paclitaxel, temozolomide), immuno-therapy by means of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors (e.g., Ipilimumab, Nivolulab, Pembrolizumab) and targeted therapy by means of BRAF and MEK inhibitors (e.g., Dabrafenib, Vemurafenib, Trametinib)) is applied for more advanced and metastatic types of the disease [6,7,11].…”

Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells

“…Therefore, the effects of hyperthermia combined with DOX on the induction of apoptosis were investigated. Previous studies have shown that hyperthermia (43 °C and 45 °C) induces apoptosis through the activation of caspase 3 in B16-F10 and A375 melanoma cell lines [ 78 , 79 ]. DOX was also shown to induce apoptosis in B16-F10 melanoma cells [ 80 , 81 ].…”