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Advances in Biological Regulation May 2021Protein kinase C α (PKCα) is a ubiquitously expressed member of the PKC family of serine/threonine kinases with diverse functions in normal and neoplastic cells. Early... (Review)
Review
Protein kinase C α (PKCα) is a ubiquitously expressed member of the PKC family of serine/threonine kinases with diverse functions in normal and neoplastic cells. Early studies identified anti-proliferative and differentiation-inducing functions for PKCα in some normal tissues (e.g., regenerating epithelia) and pro-proliferative effects in others (e.g., cells of the hematopoietic system, smooth muscle cells). Additional well documented roles of PKCα signaling in normal cells include regulation of the cytoskeleton, cell adhesion, and cell migration, and PKCα can function as a survival factor in many contexts. While a majority of tumors lose expression of PKCα, others display aberrant overexpression of the enzyme. Cancer-related mutations in PKCα are uncommon, but rare examples of driver mutations have been detected in certain cancer types (e. g., choroid gliomas). Here we review the role of PKCα in various cancers, describe mechanisms by which PKCα affects cancer-related cell functions, and discuss how the diverse functions of PKCα contribute to tumor suppressive and tumor promoting activities of the enzyme. We end the discussion by addressing mutations and expression of PKCα in tumors and the clinical relevance of these findings.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cytoskeleton; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Mutation; Neoplasm Metastasis; Neoplasms; Phosphorothioate Oligonucleotides; Protein Kinase C-alpha; Signal Transduction
PubMed: 33307285
DOI: 10.1016/j.jbior.2020.100769 -
Neuro-oncology Jan 2005Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense... (Clinical Trial)
Clinical Trial
Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas.
Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.
Topics: Adult; Aged; Astrocytoma; Blood-Brain Barrier; Brain Edema; Brain Neoplasms; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Treatment Outcome
PubMed: 15701280
DOI: 10.1215/S1152851703000353 -
Genetics and Molecular Research : GMR Aug 2016In the present study, we evaluated the effects of four solutions [Dulbecco's modified Eagle's medium (DMEM), sodium lactate Ringer's injection (SLRI), phosphate-buffered...
In the present study, we evaluated the effects of four solutions [Dulbecco's modified Eagle's medium (DMEM), sodium lactate Ringer's injection (SLRI), phosphate-buffered saline (PBS), and NaCl] on the transfection of the human protein kinase C-a antisense oligonucleotide (PKC-a ASO) aprinocarsen in human lung carcinoma A549 cells. Specifically, SLRI, DMEM, PBS, or NaCl were used as the growth solutions for A549 cells, and OPTI-MEM was used as the PKC-a ASO diluent for transfection. Additionally, SLRI, DMEM, PBS, or NaCl were used as both the growth solutions and diluents for transfection. The cell viability and transfection efficiency were determined. The results demonstrated that when SLRI was used as either the growth solution or both the growth solution and diluent for aprinocarsen transfection in A549 cells, the effects were close to the best effects observed with DMEM as the growth solution and OPTI-MEM as the diluent, which supported the transfection of aprinocarsen into the cells. Moreover, SLRI resulted in higher transfection efficiency than those of PBS and NaCl. In in vitro experiments, aprinocarsen effectively induced apoptosis in A549 cells. In conclusion, SLRI may replace PBS or NaCl in clinical trials as a transfection solution readily accepted by the human body. To our knowledge, this is the first report demonstrating the use of SLRI as a transfection solution in lung-cancer cell lines.
Topics: A549 Cells; Apoptosis; Cell Survival; Culture Media; Gene Silencing; Humans; Isotonic Solutions; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C-alpha; Ringer's Lactate; Sodium Chloride; Transfection
PubMed: 27706607
DOI: 10.4238/gmr.15037650 -
Cancer Jan 2004It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense... (Clinical Trial)
Clinical Trial
A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma.
BACKGROUND
It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense oligonucleotide, has shown ability to inhibit PKC-alpha protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21-day, continuous, intravenous infusion.
METHODS
In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21-day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL).
RESULTS
Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum-sensitive group (n = 12 patients) and a platinum-resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum-sensitive group. In the platinum-resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains.
CONCLUSIONS
When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum-based regimens.
Topics: Aged; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Middle Aged; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Ovarian Neoplasms; Protein Kinase C; Protein Kinase C-alpha; Quality of Life; Self-Assessment; Thionucleotides
PubMed: 14716767
DOI: 10.1002/cncr.11909 -
Bulletin Du Cancer 2008Protein kinase C (PKC) are cytoplasmic serine-threonine kinases, analysis of their involvement in oncogenesis is complex. Deregulated expressions of certain PKC can be... (Review)
Review
Protein kinase C (PKC) are cytoplasmic serine-threonine kinases, analysis of their involvement in oncogenesis is complex. Deregulated expressions of certain PKC can be observed in various tumors, but there is great variability in the roles of these enzymes according isoform or cell type (pro- or anti-proliferative action). Although understanding of the role of PKC in tumor development is still incomplete, different agents are currently evaluated. This review discusses the available data, with special emphasis on clinical outcomes.
Topics: Cytoplasm; Indoles; Isoenzymes; Neoplasm Proteins; Neoplasms; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase Inhibitors; Staurosporine
PubMed: 18755647
DOI: 10.1684/bdc.2008.0665