Abstract
The G2/M checkpoint is an attractive pathway for targeting and sensitizing tumor cells to cancer treatment. Abrogation of the G2/M checkpoint by targeting molecules, such as checkpoint kinase 1 (chk1), increases DNA breakage and sensitizes tumor cells to anti-tumoral agents. However, most of the previously described G2/M abrogators are actually targeting the G2-M border checkpoints rather than mitotic checkpoints. This prompted us to test the effects of combined targeting of chk1 and a critical regulator of mitosis, polo-like kinase 1 (plk1). Chk1 and plk1 were found to be co-expressed in 70% of primary neoplastic tissues we examined. Asynchronized tumor cells were treated with different DNA damaging-agents to activate G1/S, S or G2/M checkpoints. Either chk1 or plk1-specific antisense oligodeoxynucleotides (ASODN) enhanced DNA damaging agent-induced apoptosis. When used in combination, however, chk1- plus plk1-specific ASODN failed to produce synergistic effects. Moreover, selective targeting of plk1 or chk1 in tumor xenografts of mice by oncolytic adenovirus mutants demonstrated potent anti-tumoral efficacy in the presence of low dose cisplatin. Again, combined targeting of chk1 and plk1 did not further enhance anti-tumoral efficacy. We concluded that combined targeting of chk1 and plk1 was not superior to either targeting chk1 or plk1 alone, which suggested that chk1 and plk1 silencing might overlap in their mechanism of action. Whether combined targeting of chk1 with other, more specific mitotic regulators would synergistically sensitize tumor to anti-neoplastic therapeutics needs to be further clarified.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma / metabolism
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Carcinoma / pathology
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Cell Cycle / physiology
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology*
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Cervix Uteri / metabolism
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Cervix Uteri / pathology
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Checkpoint Kinase 1
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Cisplatin / pharmacology*
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Cisplatin / therapeutic use
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DNA Damage / drug effects
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DNA Damage / physiology
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Drug Synergism
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Endometrial Neoplasms / metabolism
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Endometrial Neoplasms / pathology
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Endometrium / metabolism
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Endometrium / pathology
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Female
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HL-60 Cells
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HeLa Cells
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Humans
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / mortality
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Mice
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Mice, Nude
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / radiotherapy*
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Oligodeoxyribonucleotides, Antisense / therapeutic use
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Ovary / metabolism
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Ovary / pathology
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Polo-Like Kinase 1
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Protein Kinases / metabolism
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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RNA Interference / physiology*
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Survival Analysis
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Tumor Cells, Cultured
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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Cell Cycle Proteins
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Oligodeoxyribonucleotides, Antisense
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Proto-Oncogene Proteins
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Protein Serine-Threonine Kinases
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Cisplatin