Abstract
Malignant melanoma is one of the most deadly types of solid cancers, a property mainly attributed to its highly aggressive metastatic form. On the other hand, different classes of isothiocyanates, a class of phytochemicals, present in cruciferous vegetables have been characterized by considerable anti-cancer activity in both in vitro and in vivo experimental models. In the current study, we investigated the anti-cancer response of five isothiocyanates in an in vitro model of melanoma consisting of non-metastatic (A375, B16F-10) and metastatic (VMM1, Hs294T) malignant melanoma as well as non-melanoma epidermoid carcinoma (A431) and non-tumorigenic melanocyte-neighboring keratinocyte (HaCaT) cells. Our aim was to compare different endpoints of cytotoxicity (e.g., reactive oxygen species, intracellular glutathione content, cell cycle growth arrest, apoptosis and necrosis) descriptive of an anti-cancer response between non-metastatic and metastatic melanoma as well as non-melanoma epidermoid carcinoma and non-tumorigenic cells. Our results showed that exposure to isothiocyanates induced an increase in intracellular reactive oxygen species and glutathione contents between non-metastatic and metastatic melanoma cells. The distribution of cell cycle phases followed a similar pattern in a manner where non-metastatic and metastatic melanoma cells appeared to be growth arrested at the G2/M phase while elevated levels of metastatic melanoma cells were shown to be at sub G1 phase, an indicator of necrotic cell death. Finally, metastatic melanoma cells were more sensitive apoptosis and/or necrosis as higher levels were observed compared to non-melanoma epidermoid carcinoma and non-tumorigenic cells. In general, non-melanoma epidermoid carcinoma and non-tumorigenic cells were more resistant under any experimental exposure condition. Overall, our study provides further evidence for the potential development of isothiocyanates as promising anti-cancer agents against non-metastatic and metastatic melanoma cells, a property specific for these cells and not shared by non-melanoma epidermoid carcinoma or non-tumorigenic melanocyte cells.
Highlights
Malignant melanoma (MM) is one of the deadliest types of malignancies, and it is characterized by continuously increasing rates worldwide [1,2,3,4,5]
We have adopted these conditions in order to evaluate if the previously documented cytotoxic capacity of ITCs [16,17] is mediated through perturbations in levels of reactive oxygen species (ROS), GSH, apoptosis, and necrosis as well as changes in cell cycle growth arrest kinetics
We have provided evidence that major ITC compounds (e.g., SFN, IBN, AITC, BITC and PEITC) exert a differential anti-cancer response against metastatic and non-metastatic melanoma cells, by means of increased intracellular ROS and total reduced
Summary
Malignant melanoma (MM) is one of the deadliest types of malignancies, and it is characterized by continuously increasing rates worldwide [1,2,3,4,5]. It accounts for approximately 5% of skin cancer cases, it is related to high mortality rates which account for approximately 80% of skin cancer deaths [6]. 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]. 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
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