Erika Csekes
Statement of the Problem: Cutaneous malignant melanoma is the most aggressive form of skin cancer, with a high mortality frequency. The alternative therapeutic options involve use of phytochemicals owing to their general acceptance, low side effects and pleiotropic efficacy. Moreover, chemical synthesis represents a tool how to solve the common shortcomings associated with a use of phyto-constituents, such as low stability and poor bioavailability. Enhancement of lipophilicity of a compound by substitution with hydrophobic moiety may also favor its topical/transdermal delivery. Our study presents a pre-clinical assessment of a semisynthetic p-quinol, protoapigenone 1ʹ-O-butyl ether (PABut), in A375 human melanoma cell line also in comparison with natural congener, protoapigenone. The cytotoxicity was determined using MTT assay. Fluorescence-based methods assisted by flow cytometry were used to asses the levels of reactive oxygen species (ROS) induced by the compounds tested, their influence of cell cycle distribution and apoptosis in melanoma A375 cells. Markers of senescence were evaluated by light microscopy, spectrofluorimetry and by Western blot analysis. PABut showed a remarkable cytotoxicity against A375 cells comparable to protoapigenone, accompanied by cell cycle arrest in G2/M phase. However, PABut showed a more profound ROS-promoting effect than protoapigenone accompanied by increase of early apoptosis. The selectivity index of PABut was comparable to doxorubicin. Unlike unmodified protoflavone, PABut significantly decreased protein expression of NAD-dependent deacetylase SirT1 and β-actin. This was followed by PABut-induced significant increase of expression of SOD2 enzyme and significant elevation of senescence markers, p21 and p16 proteins and SA-β-Gal. Conclusion & Significance: These results suggest that PABut exerts high chemotherapeutic potential in melanoma cells involving prooxidant and pro-senescent effect and is suitable for further testing. This work was supported by the Slovak Research and Development Agency under the Contract no. APVV-18-0336, VEGA 2/0041/17, NKFIH grant K119770, grant 20391-3/2018/FEKUSTRAT and COST Action CM1407.
Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.
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