Although previous studies have demonstrated the stimulatory role of melanin on HIF-1α expression in melanoma cells [4], it seems that enhancing effect of the combination therapy on melanin production (Fig 5) might contribute to the anti-oxidant action of SIM and DMXAA on the cell co-culture microenvironment (Fig 4) and finally, to the suppression of HIF-1α production in these tumor cells (Fig 6A and 6B). Here, HIF1A is linked to neoplasm.