Abstract
MK-1775 is a potent and selective small molecule Wee1 inhibitor. Previously we have shown that it abrogated DNA damaged checkpoints induced by gemcitabine, carboplatin, and cisplatin and enhanced the anti-tumor efficacy of these agents selectively in p53-deficient tumor cells. MK-1775 is currently in Phase I clinical trial in combination with these anti-cancer drugs. In this study, the effects of MK-1775 on 5-fluorouracil (5-FU) and other DNA-damaging agents with different modes of action were determined. MK-1775 enhanced the cytotoxic effects of 5-FU in p53-deficient human colon cancer cells. MK-1775 inhibited CDC2 Y15 phosphorylation in cells, abrogated DNA damaged checkpoints induced by 5-FU treatment, and caused premature entry of mitosis determined by induction of Histone H3 phosphorylation. Enhancement by MK-1775 was specific for p53-deficient cells since this compound did not sensitize p53-wild type human colon cancer cells to 5-FU in vitro. In vivo, MK-1775 potentiated the anti-tumor efficacy of 5-FU or its prodrug, capecitabine, at tolerable doses. These enhancements were well correlated with inhibition of CDC2 phosphorylation and induction of Histone H3 phosphorylation in tumors. In addition, MK-1775 also potentiated the cytotoxic effects of pemetrexed, doxorubicin, camptothecin, and mitomycin C in vitro. These studies support the rationale for testing the combination of MK-1775 with various DNA-damaging agents in cancer patients.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antimetabolites, Antineoplastic / pharmacology*
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Camptothecin / pharmacology
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Capecitabine
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Caspases / metabolism
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / metabolism
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Cell Proliferation / drug effects
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / pathology*
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DNA Damage / drug effects*
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Doxorubicin / pharmacology
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Flow Cytometry
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Fluorouracil / analogs & derivatives
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Fluorouracil / pharmacology*
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Glutamates / pharmacology
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Guanine / analogs & derivatives
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Guanine / pharmacology
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Histones / metabolism
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Humans
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Immunoenzyme Techniques
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Mitomycin / pharmacology
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Pemetrexed
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology*
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Pyrimidinones
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Rats
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Rats, Inbred F344
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Rats, Nude
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Xenograft Model Antitumor Assays
Substances
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Antibiotics, Antineoplastic
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Antimetabolites, Antineoplastic
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Antineoplastic Agents, Phytogenic
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Cell Cycle Proteins
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Glutamates
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Histones
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Nuclear Proteins
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Pyrazoles
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Pyrimidines
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Pyrimidinones
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Pemetrexed
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Deoxycytidine
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Mitomycin
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Guanine
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Capecitabine
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Doxorubicin
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Protein-Tyrosine Kinases
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WEE1 protein, human
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Caspases
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adavosertib
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Fluorouracil
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Camptothecin