Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA
✍ Scribed by Róisín NicAmhlaoibh; Mary Heenan; Irene Cleary; Samantha Touhey; Colette O'Loughlin; Carmel Daly; Gabriel Nuñez; Kevin J. Scanlon; Martin Clynes
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- French
- Weight
- 336 KB
- Volume
- 82
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
An in vitro model that might be relevant to cancer cell chemoresistance in vivo was generated by exposing the human lung carcinoma clonal cell line DLKP-SQ to 10 sequential pulses of pharmacologically attainable doses of doxorubicin. The resistant variant, DLKP-SQ/10p, was found to be cross-resistant to doxorubicin (10؋), vincristine (43؋), etoposide (3؋), sodium arsenate (3؋), paclitaxel (38؋) [which could imply overexpression of P-glycoprotein (P-gp) and possibly increased multidrug resistance-associated protein activity] and 5-fluorouracil (4؋), but slightly sensitized to carboplatin. Analysis of mRNA levels in the resistant variant revealed overexpression of mdr1 mRNA without significant alteration in mrp, Topo. II␣, GST, dhfr or thymidylate synthase mRNA levels. Overexpression of the anti-apoptotic bcl-x L transcript and the pro-apoptotic bax mRNA was also detected but no alterations in bcl-2 or bag-1 mRNA levels were observed. Resistance to a P-gp-associated drug, doxorubicin, could be reversed with P-gp circumventing agents such as cyclosporin A and verapamil, but these substances had no effect on resistance to 5-fluorouracil. Overexpression of the pro-apoptotic bcl-x S gene in the DLKP-SQ/10p line partially reversed resistance not only to P-gp-associated drugs but also to 5-fluorouracil, indicating that the ratio of bcl family members may be important in determining sensitivity to chemotherapeutic drug-induced apoptosis.