The tumor microenvironment is characterized by
cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic
tumor zones contain clusters of
cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic
melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G1-arrested
melanoma cells, irrespective of the underlying cause mediating G1 arrest, are resistant to apoptosis induced by the
proteasome inhibitor bortezomib or the
alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to
mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of
melanoma cells with a
mitogen-activated protein kinase pathway inhibitor, which induced G1 arrest, resulted in resistance to
temozolomide or
bortezomib. On the other hand, pretreatment with
temozolomide, which induced G2 arrest, did not result in resistance to
mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of
melanoma cells that has implications on the choice and timing of
drug combination therapies.