Effect of modulation of protein kinase C activity on cisplatin cytotoxicity in cisplatin-resistant and cisplatin-sensitive human osteosarcoma cells

doi:10.1016/0304-3835(93)90010-7

Cancer Letters

Volume 72, Issues 1–2, 16 August 1993, Pages 53-58

https://doi.org/10.1016/0304-3835(93)90010-7 Get rights and content

Abstract

The effect of modulation of protein kinase C (PKC) activity by 12-O-tetradecanoylphorbol-13-acetate (TPA) on cisplatin cytotoxicity was examined in a human osteosarcoma U2-OS cell line and in a U2-OS variant (U2-OS/Pt) selected after continuous exposure to increasing concentrations of cisplatin. U2-OS/Pt cells showed a 7.5-fold resistance to the drug. A 24 h exposure of cells to TPA caused a potentiation of cisplatin cytotoxicity in sensitive and in resistant cells; under these conditions, PKC activity was shown to be downregulated. In contrast, a short-term exposure of cells to TPA did not affect cisplatin cytotoxicity in U2-OS or in U2-OS/Pt cells. These results support the involvement of PKC in cellular response to cisplatin. However, this enzyme is probably not directly implicated in the mechanisms of acquired resistance in this cell system.

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Cited by (9)

Targeting protein kinase C in sarcoma
2014, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
Osteosarcoma (OS) is the most common primary high-grade sarcoma of bone with a peak incidence occurring in children aged 10–14 years and a second smaller peak in adults over 40 [56]. The cellular roles of the PKC family of proteins in OS have long been reported and include the cellular response to cisplatin [57], induction of differentiation [58], growth, survival and metastases [59]. Osteosarcomatous growth could be dependent on PKCδ which has been shown to be necessary for fibroblast growth factor (FGF) induced bone development by controlling the expression and post-translational modification of RUNX2 [60,61].
Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure–function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic.
Molecular alterations of cells resistant to platinum drugs: Role of PKCα
2006, Biochimica et Biophysica Acta - Molecular Cell Research
Development of resistance to platinum compounds may involve not only overexpression of defence mechanisms but also alterations in cellular response to the drug-induced genotoxic stress. To investigate the cellular bases of response to platinum compounds, we examined the profile of gene expression of ovarian carcinoma cells exhibiting sensitivity (A2780) or resistance (A2780/BBR3464) to platinum compounds. Using display PCR, we found that acquisition of resistance to the multinuclear platinum complex BBR3464 was associated with modulation of several transcripts, including up-regulation of the major substrate of protein kinase C (PKC), the myristoylated alanine-rich C kinase substrate (MARCKS). This feature was associated with PKCα down-regulation. To explore the role of PKCα in cellular sensitivity to platinum compounds, resistant cells were transfected with a PKCα-containing vector. PKCα-overexpressing resistant cells exhibited a decrease in sensitivity to cisplatin, whereas no significant change in sensitivity to BBR3464 was observed. A number of approaches designed to modulate the function or expression of PKCα support that the isoenzyme may play a role in determining resistance only to cisplatin but not to BBR3464, which is known to activate a different pathway of cell response. In conclusion, in spite of PKCα down-regulation in our model, its regulatory function was not apparently implicated in the development of resistance to platinum compounds and the present results do not support a general role of PKCα as a determinant of the resistance status.
Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: A New York Gynecologic Oncology Group study
2004, Gynecologic Oncology
Objective. Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1–cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma.
Methods. An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50–65 μg/m²) as a 1-h infusion followed by cisplatin (50 mg/m²). The combined treatment was administered every 21 days.
Results. Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 μg/m² and 50% received bryostatin at 65 μg/m². Seventy-one percent completed two cycles of treatment. The most common grade II–III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses.
Conclusion. Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.
Nucleolar targeting by platinum: P53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction
2015, Molecular Pharmaceutics
Phase i study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
2009, Cancer Chemotherapy and Pharmacology
Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines
2002, Anti-Cancer Drugs

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Cancer Letters

Abstract

References (22)

Involvement of protein kinase C in phorbol ester-induced sensitization of HeLa cells to cis-diamminedichloroplatinum(II)

J. Biol. Chem.

Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters

J. Biol. Chem.

Longterm phorbol ester treatment down-regulates protein kinase C and sensitizes the phosphoinositide signalling pathway to hormone and growth factor stimulation

J. Biol. Chem.

Resistance to platinum compounds: mechanisms and beyond

Eur. J. Cancer Clin. Oncol.

Hormone- and tumor-promoter-induced activation or membrane association of protein kinase C in intact cells

Meth. Enzymol.

Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance

Cancer Cells

Verapamil reversal of doxorubicin resistance in multidrug-resistant human myeloma cells and association with drug accumulation and DNA damage

Cancer Res.

Activation of programmed cell death by anticancer agents: cisplatin as a model system

Cancer Cells

Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C

Int. J. Cancer

Synergistic enhancement of the antiproliferative activity of cis-diamminedichloroplatinum(II) by the ether lipid analogue BM41440, an inhibitor of protein kinase C

Lipids

Response to adversity: molecular control of gene activation following genotoxic stress

New Biol.

Cited by (9)

Targeting protein kinase C in sarcoma

Molecular alterations of cells resistant to platinum drugs: Role of PKCα

Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: A New York Gynecologic Oncology Group study

Nucleolar targeting by platinum: P53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction

Phase i study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors

Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines