title: Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy.
abstract: BACKGROUND
  Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit.
  
  
  METHODS
  We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers.
  
  
  RESULTS
  As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect.
  
  
  CONCLUSIONS
  The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Szulkin
authors.forename: Gustav
authors.initials: G
authors.lastname: Nilsonne
authors.forename: Filip
authors.initials: F
authors.lastname: Mundt
authors.forename: Agata M
authors.initials: AM
authors.lastname: Wasik
authors.forename: Pega
authors.initials: P
authors.lastname: Souri
authors.forename: Anders
authors.initials: A
authors.lastname: Hjerpe
authors.forename: Katalin
authors.initials: K
authors.lastname: Dobra
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D000068437:Pemetrexed; D011719:Pyrazines / Q000494:pharmacology*; D020887:Selenious Acid / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D000069286:Bortezomib; D016190:Carboplatin; D003841:Deoxycytidine; D004317:Doxorubicin; D005971:Glutamates; D006147:Guanine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000068437:Pemetrexed; D011719:Pyrazines; D020887:Selenious Acid; D000093542:Gemcitabine; C118895:SLC7A11 protein, human; C421109:multidrug resistance-associated protein 1