Pyridinium derivatives for metastatic melanoma therapy

Melanoma incidence is increasing faster than any other form of cancer in the world today. Early detection is often curative with surgery, but late stage melanoma is lethal. This lethality is attributed to melanoma developing resistance to all Food and Drug Administration approved treatment options. Therefore, there is a critical need to improve treatments options that result in long-term survival for melanoma patients.

One approach to melanoma therapy involves exploiting differences in melanoma cell metabolism relative to normal cells. Although cellular metabolism is a universal process that is required to maintain cellular function and survival, there are fundamental differences between cancer and normal cell metabolism, such as differences in mitochondrial membrane potential, which may be exploited for a therapeutic strategy. The research presented here explores a new class of drugs that target the metabolic differences between melanoma cells and normal cells as a way to selectively kill melanoma cells. Specifically, the drugs used in this study preferentially accumulate in the mitochondria of melanoma cells via attraction to the increased mitochondrial membrane potential in melanoma cells relative to normal cells. Importantly, the drugs presented here have not been studied in this context before, and provide a way to visualize cancer cell targeting due to their ability to fluoresce upon accumulation in the mitochondrial membrane. Results demonstrate that the type of compounds examined can be designed to inhibit mitochondria metabolism that ultimately results in melanoma cell death, demonstrating the potential of a mitochondrial-targeted therapy for metastatic melanoma.