Inhibition of telomerase increases resistance of melanoma cells to temozolomide, but not to temozolomide combined with poly (adp-ribose) polymerase inhibitor.
In the present study, we have investigated the influence of telomerase inhibition in chemosensitivity of melanoma cells to temozolomide (TMZ), a methylating agent with promising antitumor activity against metastatic melanoma. In fact, telomerase, a ribonucleoprotein enzyme expressed in the majority of tumors, is presently considered an attractive target for anticancer therapy, with the double aim of reducing tumor growth and increasing chemosensitivity of cancer cells. Susceptibility to TMZ and to other antitumor agents used for treatment of metastatic melanoma was initially assessed in melanoma lines with different basal levels of telomerase activity. Thereafter, chemosensitivity was investigated after inhibition of telomerase by means of stable transfection of a catalytically inactive, dominant-negative mutant of hTERT (DN-hTERT). This study shows for the first time that: a) susceptibility to TMZ of melanoma lines derived from the same patient did not depend on basal telomerase activity; b) inhibition of telomerase by DN-hTERT resulted in reduced growth rate and increased resistance to TMZ and to the chloroethylating agent carmustine, increased sensitivity to cisplatin, and no change in response to tamoxifen or to a selective N3-adenine methylating agent; c) inhibition of poly(ADP-ribose) polymerase (PARP), an enzyme involved in the repair of N-methylpurines, restored sensitivity of DN-hTERT clones to TMZ. These results indicate that a careful selection of the antitumor agent has to be made when antitelomerase therapy is combined with chemotherapy. Moreover, the data presented here suggest that TMZ + PARP inhibitor combination is active against telomerase-suppressed and slowly growing tumors.
Tentori
Lucio
L
Department of Neuroscience, University of Rome "Tor Vergata", Rome, Italy.
Portarena
Ilaria
I
Barbarino
Marcella
M
Balduzzi
Alessandra
A
Levati
Lauretta
L
Vergati
Matteo
M
Biroccio
Annamaria
A
Gold
Barry
B
Lombardi
Maria Luisa
ML
Graziani
Grazia
G
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D011088:DNA Ligases / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077204:Temozolomide; D014162:Transfection; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013450:Sulfones; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D019098:Telomerase; D011088:DNA Ligases; D002330:Carmustine; D000077204:Temozolomide