Bcl-x(L) confers multi-drug resistance in several squamous cell carcinoma cell lines

Carboplatin (CBDCA) alone or in combination with irradiation and other chemotherapeutic agents has been used for the treatment of oral squamous carcinoma. However, there are some limitations for such therapy because of inherent or acquired resistance to CBDCA. To gain some insights into the association of CBDCA resistance with Bcl-2 family level or p53 status, we established eight carcinoma cell lines, consisting of two resistant (MIT8, MIT16), two sensitive (MIT6, MIT7), and four intermediate lines. All of the five cell lines with p53 mutation belonged to the resistant approximately intermediate group, whereas two of three other lines with wild-type p53 were in the sensitive group. Interestingly, both of the two resistant cell lines showed elevated levels of Bcl-x(L), almost double that of sensitive line (MIL5), whereas either Bcl-2 or Bax-alpha level did not correlate with the CBDCA-resistance. To further verify the association between the Bcl-x(L) level and the drug resistance, two transformants (x(L)-3, x(L)-6) overexpressing Bcl-x(L) in the CBDCA-sensitive cell line MIT7 were established using the gene transfer method. Both clones showed resistance to multiple chemotherapeutic agents, including CBDCA, actinomycin D, etoposide, and mitomycin C. Moreover, MIT8 and MT16 also displayed cross-resistance to these agents. These findings suggest that Bcl-x(L) may function as one of the key components conferring multiple drug-resistance in squamous cell carcinomas.