Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness.
A melphalan-resistant variant (Roswell Park Memorial Institute (RPMI)-2650Ml) and a paclitaxel-resistant variant (RPMI-2650Tx) of the drug-sensitive human nasal carcinoma cell line, RPMI-2650, were established. The multidrug resistance (MDR) phenotype in the RPMI-2650Tx appeared to be P-glycoprotein (PgP)-mediated. Overexpression of multidrug resistant protein (MRP) family members was observed in the RPMI-2650Ml cells, which were also much more invasive in vitro than the parental cell line or the paclitaxel-resistant variant. Increased expression of alpha(2), alpha(5), alpha(6), beta(1) and beta(4) integrin subunits, decreased expression of alpha(4) integrin subunit, stronger adhesion to collagen type IV, laminin, fibronectin and matrigel, increased expression of MMP-2 and MMP-9 and significant motility compared with the parental cells were observed, along with a high invasiveness in the RPMI-2650Ml cells. Decreased expression of the alpha(2) integrin subunit, decreased attachment to collagen type IV, absence of cytokeratin 18 expression, no detectable expression of gelatin-degrading proteases and poor motility may be associated with the non-invasiveness of the RPMI-2650Tx variant. These results suggest that melphalan exposure can result in not only a MDR phenotype, but could also make cancer cells more invasive, whereas paclitaxel exposure resulted in MDR without increasing the in vitro invasiveness in the RPMI-2650 cells.
Liang
Y
Y
National Cell and Tissue Culture Center/National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9, Dublin, Ireland.
Meleady
P
P
Cleary
I
I
McDonnell
S
S
Connolly
L
L
Clynes
M
M
D015703:Antigens, CD / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015153:Blotting, Western; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008558:Melphalan / Q000627:therapeutic use*; D008562:Membrane Glycoproteins; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060245:Tetraspanin 29; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; C554869:CD9 protein, human; D016023:Integrins; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D017239:Paclitaxel; D008558:Melphalan