The effect of combination treatment of vascular endothelial growth factor receptor 3 inhibitor, MAZ-51, and zingerone on melanoma cell proliferation

Abstract

Melanoma is an aggressive form of skin cancer that is characterised by the carcinogenic transformation of melanocytes. Globally approximately 132 000 new melanoma cases are recorded annually and South Africa has recorded an incidence of 2.7 per 100 000 individuals. Various treatment strategies such as chemotherapy, targeted therapy and surgical excision are currently employed to inhibit melanoma growth, survival and progression however, the use of current treatments often results in unintended side-effects and drug resistance. Therefore, to combat this negative effect alternative treatment strategies such as medicinal plants and their bioactive phytochemicals have been widely studied and accepted as an alternative treatment, suggesting that the combined use of phytochemicals and synthetic drugs may inhibit cancer growth and proliferation with limited toxicity observed to noncancerous cells. Therefore, this study aims to investigate the individual and combined effects of (3-(4-Dimethylamino-naphthelen-1-ylmethylene)-1, 3-hydroindol-2-one) (MAZ-51) and a derivative of ginger, zingerone, on melanoma cell proliferation and survival in the melanoma (B16-F10) and human keratinocyte (HaCaT) cell lines. The cytotoxic effects of MAZ-51 (0.002-0.005 mg/mL) and zingerone (0.5-2 mg/mL) at 24, 48 and 72 hours were investigated using crystal violet assay. Additionally, crystal violet analysis was used to investigate the effects of MAZ-51 and zingerone co-treated with vascular endothelial growth factor (VEGF) on cell numbers. The morphological changes induced by the compounds were investigated using polarization optical transmitted differential contrast (PlasDIC) and hematoxylin and eosin (H&E) staining. The effects of the compounds on cell cycle progression were determined using flow cytometry. The results indicate that MAZ-51 and zingerone significantly inhibited cell growth at 48 and 72 hours (p<0.05). Morphological changes included the formation of apoptotic bodies, cellular protrusions, cell swelling and cell rounding suggesting cell death. In addition, MAZ-51 and zingerone resulted in a cell cycle block. Our findings demonstrate that MAZ-51 and zingerone exhibit significant antiproliferative effects on melanoma cells, with zingerone showing potential in reducing melanoma cell viability.