title: Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells.
abstract: 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.
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Beaumont
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Dermatological Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Hill
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sheena M
authors.initials: SM
authors.lastname: Daignault
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Goldie Y L
authors.initials: GYL
authors.lastname: Lui
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Danae M
authors.initials: DM
authors.lastname: Sharp
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia; Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia. Electronic address: n.haass1@uq.edu.au.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry; D017209:Apoptosis; D000069286:Bortezomib / Q000737:chemistry; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000378:metabolism*; D000077204:Temozolomide
chemical_list: D000477:Alkylating Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000069286:Bortezomib; D003606:Dacarbazine; D020928:Mitogen-Activated Protein Kinases; D000077204:Temozolomide