Bcl-xL confers multi-drug resistance in several squamous cell carcinoma cell lines

Noutomi, T.; Chiba, H.; Itoh, M.; Toyota, H.; Mizuguchi, J.

Next »Oral Oncology
Volume 38, Issue 1 , Pages 41-48, January 2002

Bcl-x_L confers multi-drug resistance in several squamous cell carcinoma cell lines

T. Noutomi
- Department of Oral & Maxillofacial-Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
H. Chiba
- Department of Oral & Maxillofacial-Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
M. Itoh
- Department of Oral & Maxillofacial-Surgery, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
H. Toyota
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
- Intractable Disease Research Center, Tokyo Medical University, Tokyo, Japan
J. Mizuguchi
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
- Intractable Disease Research Center, Tokyo Medical University, Tokyo, Japan
- Corresponding author. Tel.: +81-3-3351-6141; fax: +81-3-3341-2941

Received 13 July 2000; accepted 4 September 2000.

Abstract

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 ∼ 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-α 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.

Keywords: Squamous cell carcinoma, Apoptosis, Carboplatin, Bcl-x_L, Bax-α