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Role of protein kinases in antitumor drug resistance
1Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Austria.
Abstract:
The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.
Insights
Protein kinases regulate proteins involved in antitumor drug resistance, including P-glycoprotein and topoisomerase II. Inhibiting these kinases may reduce multidrug resistance and enhance chemotherapy effectiveness.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Protein phosphorylation regulates key proteins in antitumor drug resistance.
- Proteins like P-glycoprotein (Pgp) and topoisomerase II (topo II) are implicated in multidrug resistance (MDR).
- Transcriptional regulation of drug resistance proteins involves protein kinase C (PKC) and casein kinase II (CKII).
Purpose of the Study:
- To review evidence on protein phosphorylation in antitumor drug resistance.
- To describe attempts to modulate MDR using protein kinase C inhibitors.
- To explore protein kinases as targets for reducing drug resistance.
Main Methods:
- Review of existing literature on protein phosphorylation and drug resistance.
- Description of experiments using protein kinase C inhibitors (e.g., ilmofosine).
- Analysis of synergistic effects of protein kinase inhibitors with chemotherapy agents like cis-platinum.
Main Results:
- Protein kinases, including PKC and CKII, regulate the expression of MDR-associated proteins (Pgp, metallothionein, GST, dTMP synthase, Fos, Jun).
- Ras activation of protein kinase cascades drives the expression of drug resistance genes.
- Inhibition of PKC reduced ras-induced Fos expression and enhanced cis-platinum cytotoxicity.
Conclusions:
- Protein kinases are critical regulators of multidrug resistance.
- Targeting protein kinases offers a potential strategy to overcome or prevent drug resistance in cancer therapy.
- Modulating kinase activity can enhance the efficacy of existing chemotherapeutic agents.