A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells

Innate factors such as β-defensins may exhibit anti-cancer functions, serving as a first line of defense against incipient or dormant cancer cells. In previous studies, our lab demonstrated that hemoglobin-derived factors such as the hemoglobin beta chain or an alpha/beta heterodimer of hemoglobin trigger apoptosis and necrosis in neuroblastoma and brain-metastasizing melanoma cells, respectively. In addition to its cytotoxic function, the alpha/beta hemoglobin dimer downregulated the expression of proteins such as BRD4 and IRS2, which perform essential functions in tumorigenesis and cancer progression. In the present study, we proved the concept, raised for the first time in this study, that in addition to their anti-cancer functions, innate resistance factors could serve as pathfinders to identify theranostic targets on progressing cancer cells. we used small-molecule inhibitors of the above proteins as potential anti-brain-metastasizing melanoma cell agents. Indeed, a combination of sub-lethal concentrations of BRD4 and IRS2 inhibitors synergistically arrested melanoma cells at the subG1 phase of the cell cycle, killed more than 70% of such cells, and attenuated the virulence of brain-metastasizing melanoma cells.