Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance

Cinzia Lanzi, Paola Perego, Rosanna Supino, Simona Romanelli, Tiziana Pensa, Nives Carenini, Ilario Viano, Donato Colangelo, Roberto Leone, Piero Apostoli, Giuliana Cassinelli, Romolo A. Gambetta, Franco Zunino

Research output: Contribution to journalArticle

Abstract

In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A431/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin- resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.

Original languageEnglish
Pages (from-to)1247-1254
Number of pages8
JournalBiochemical Pharmacology
Volume55
Issue number8
DOIs
Publication statusPublished - Apr 15 1998

Keywords

  • Apoptosis
  • Cervix squamous cell carcinoma
  • Cisplatin
  • DNA damage
  • Drug resistance

ASJC Scopus subject areas

  • Pharmacology

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    Lanzi, C., Perego, P., Supino, R., Romanelli, S., Pensa, T., Carenini, N., Viano, I., Colangelo, D., Leone, R., Apostoli, P., Cassinelli, G., Gambetta, R. A., & Zunino, F. (1998). Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance. Biochemical Pharmacology, 55(8), 1247-1254. https://doi.org/10.1016/S0006-2952(97)00599-6