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Study of therapy resistance in cancer cells with functional proteome analysis
Julia Poland1, Dirk Schadendorf, Hermann Lage
1Institut für Laboratoriumsmedizin und Pathobiochemie, Universitätsklinikum Charité, Berlin, Germany.
Abstract:
Different types of cancer are naturally resistant to many anticancer drugs. Additionally, these tumours develop acquired drug resistance, which includes the classical multidrug resistance (MDR) accompanied by the synthesis of P-glycoprotein, a member of the superfamily of ATP-binding cassette (ABC) transporters. Furthermore, atypical MDR is mediated by several different, some unknown, mechanisms. To overcome chemoresistance problems, antineoplastic drugs are often combined with other modes of therapy, e.g. hyperthermia, where good response has been reported in several experimental tumour models and in advanced cancer patients. The success of this combined anticancer treatment may be limited by an increase in chemoresistance and thermoresistance. A model system to study resistance phenomena is the use of chemoresistant and thermoresistant cancer cell lines. We have established chemoresistant cancer cell lines (gastric and pancreatic carcinoma, fibrosarcoma, melanoma) and now thermoresistant cell lines derived from gastric and pancreatic carcinoma cells and their counterparts that were resistant towards daunorubicin (classical MDR) and mitoxantrone (atypical MDR). Using proteomics, in this paper we evaluate the drug resistance of chemoresistant melanoma cells (parental cell line MeWo and sublines exhibiting drug resistance towards etoposide, cisplatin, fotemustine and vindesine) as a paradigm for analysis of drug resistance phenomena. Additionally, we investigate heat resistance and the interaction of chemoresistance and thermoresistance to identify common pathways using the parental and drug resistant stomach cancer cell lines EPG85-257, EPG85-257RNOV, EPG85-257RDB and their thermoresistant counterparts. Possible implications of differential protein expression will be discussed.
Insights
Cancer cells develop resistance to drugs and heat, limiting combined therapies. This study uses proteomics to analyze drug and heat resistance in cancer cell lines, seeking common pathways to overcome treatment challenges.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer cells exhibit natural and acquired resistance to anticancer drugs, including multidrug resistance (MDR) mediated by P-glycoprotein.
- Atypical MDR involves various, sometimes unknown, mechanisms.
- Combining chemotherapy with hyperthermia shows promise but can be limited by increased chemoresistance and thermoresistance.
Purpose of the Study:
- To investigate drug resistance mechanisms in chemoresistant melanoma cells using proteomics.
- To analyze heat resistance and the interplay between chemoresistance and thermoresistance in gastric cancer cell lines.
- To identify common molecular pathways underlying combined chemo- and thermoresistance.
Main Methods:
- Establishment of chemoresistant and thermoresistant cancer cell lines (gastric, pancreatic carcinoma, fibrosarcoma, melanoma).
- Proteomic analysis of drug-resistant melanoma sublines and gastric cancer cell lines.
- Comparative analysis of parental and resistant cell lines to identify differential protein expression.
Main Results:
- Proteomics was employed to evaluate drug resistance in chemoresistant melanoma cells.
- Heat resistance and chemoresistance interactions were investigated in gastric cancer cell lines.
- Differential protein expression patterns were analyzed to understand resistance phenomena.
Conclusions:
- Proteomics offers a valuable approach to analyzing complex drug resistance phenomena in cancer.
- Understanding the interplay between chemoresistance and thermoresistance is crucial for optimizing combination therapies.
- Identifying common pathways may lead to novel therapeutic strategies to overcome treatment resistance.