Abstract
Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs). Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite). We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT-sensitive and -resistant tumor models. Gain- and loss-of-function experiments established a direct role for PLK1 in counteracting SN38 antiproliferative and pro-apoptotic effects. The ability to activate an efficient G2/M cell cycle checkpoint allowing PLK1 ubiquitination and degradation was found associated with SN38-induced apoptosis in SCC cells. However, the synergistic interaction between SN38 and BI2536 enhanced apoptosis in cell lines both sensitive and resistant to SN38-induced apoptotic cell death. A well-tolerated CPT11/BI2536 cotreatment resulted in improved antitumor effect against SCC xenografts in mice compared to single agent treatments. The increased apoptosis induction was reflected in a high rate of complete responses and cures in mice harboring SCC, including tumors with intrinsic or acquired resistance to CPTs. PLK1 inhibition represents a promising strategy to improve the antitumor efficacy of CPT11-based regimens.
Keywords:
BI2536; CPT11; PLK1; combination treatment; squamous cell carcinoma.
MeSH terms
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Activation, Metabolic
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Camptothecin / metabolism
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Camptothecin / pharmacology
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Carcinoma, Squamous Cell / pathology*
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cell Line, Tumor
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Child
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Drug Resistance, Neoplasm / physiology*
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Female
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Irinotecan
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Mice
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Mice, Nude
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Molecular Targeted Therapy*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Polo-Like Kinase 1
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Prodrugs / administration & dosage
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Prodrugs / metabolism
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Prodrugs / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proteolysis
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Pteridines / administration & dosage
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Pteridines / pharmacology*
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Rhabdomyosarcoma, Embryonal / pathology*
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Sarcoma, Ewing / pathology*
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Skin Neoplasms / pathology*
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Topoisomerase I Inhibitors / metabolism
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Topoisomerase I Inhibitors / pharmacology*
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Ubiquitination
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Uterine Cervical Neoplasms / pathology*
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Xenograft Model Antitumor Assays
Substances
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BI 2536
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Cell Cycle Proteins
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Neoplasm Proteins
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Prodrugs
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pteridines
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Topoisomerase I Inhibitors
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Irinotecan
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Protein Serine-Threonine Kinases
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Camptothecin