Telomerase Activity and Telomere Length in Human Tumor Cells with Acquired Resistance to Anticancer Agents

Abstract

Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. In this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. These included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line(AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance too there cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but the seme chanisms of resistance could not be related to drug efflux pump expression, GSH levels or PARP cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should betaken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.

Keywords:

• Telomerase activity
• telomere length
• drug resistance
• P-glycoprotein
• glutathione
• MRP1
• PARP cleavage
• anticancer drugs