Abstract
Malignant melanoma is still a serious medical problem. Relatively high mortality, a still-growing number of newly diagnosed cases, and insufficiently effective methods of therapy necessitate melanoma research. Tetracyclines are compounds with pleiotropic pharmacological properties. Previously published studies on melanotic melanoma cells ascertained that minocycline and doxycycline exerted an anti-melanoma effect. The purpose of the study was to assess the anti-melanoma potential and mechanisms of action of minocycline and doxycycline using A375 and C32 human amelanotic melanoma cell lines. The obtained results indicate that the tested drugs inhibited proliferation, decreased cell viability, and induced apoptosis in amelanotic melanoma cells. The treatment caused changes in the cell cycle profile and decreased the intracellular level of reduced thiols and mitochondrial membrane potential. The exposure of A375 and C32 cells to minocycline and doxycycline triggered the release of cytochrome c and activated initiator and effector caspases. The anti-melanoma effect of analyzed drugs appeared to be related to the up-regulation of ERK1/2 and MITF. Moreover, it was noticed that minocycline and doxycycline increased the level of LC3A/B, an autophagy marker, in A375 cells. In summary, the study showed the pleiotropic anti-cancer action of minocycline and doxycycline against amelanotic melanoma cells. Considering all results, it could be concluded that doxycycline was a more potent drug than minocycline.
Highlights
Malignant melanoma is a skin cancer derived from highly specialized cells called melanocytes [1]
The findings indicate that A375 cells were more sensitive to the anti-melanoma effect of tested tetracyclines than C32 cells, especially for the treatment with doxycycline
Dulbecco’s modified Eagle medium (DMEM), Dulbecco’s phosphate-buffered saline (DPBS), secondary antibody—Alexa Fluor 488 and SYTO Deep Red Nucleic Acid Stain were acquired from Thermo Fisher Scientific (Waltham, MA, USA)
Summary
Malignant melanoma is a skin cancer derived from highly specialized cells called melanocytes [1]. Most melanocytes are localized in the basal layer of the epidermis. Their main function is the synthesis of the biopolymer pigment melanin, which is delivered to the surrounding keratinocytes where it protects skin cells from harmful factors [2–4]. The malignant transformation of melanocytes can be triggered by different environmental factors, including UV radiation, heavy metals, or pesticides. Geographical location, skin phototypes I and II, intermittent and intense sun exposure, numerous pigment nevi, genetic susceptibility, or immunosuppression belong to risk factors for melanoma development [5,6]. The process of melanocyte transformation to melanoma cells is based on genetic and epigenetic changes. The molecular studies of melanoma pathology have contributed to the classification, diagnosis, and targeted therapy [7,8]
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