Quinolizidinyl derivatives of iminodibenzyl and phenothiazine as multidrug resistance modulators in ovarian cancer cells

Federica Barbieri, Angela Alama, Bruno Tasso, Vito Boido, Cristina Bruzzo, Fabio Sparatore

Research output: Contribution to journalArticle

Abstract

The development of multidrug-resistance (MDR) in neoplastic cells is often responsible for the therapy failure and poor outcome of a number of human cancers. MDR may be associated with the expression of the multidrug transporter glycoprotein p170, encoded by the MDR1 gene, which acts as an ATP-dependent efflux pump by reducing the intracellular accumulation of some cytotoxic agents. A variety of iminodibenzyl and phenothiazine derivatives, characterized by the presence of a bicyclic, strongly basic, and highly lipophilic quinolizidine nucleus, were synthesized to investigate their ability to modulate the MDR phenotype. A set of 10 of them (named 1-10), bearing quinolizidine moiety linked through different connecting chains, were tested as chemoresistance- reversing agents on doxorubicin-resistant ovarian cancer cells (A2780-DX3). A 51-fold resistance to doxorubicin was reported in the A2780-DX3 compared to the parental sensitive A2780 WT with mean IC50 values of 0.02 and 1.02 μM, respectively. Moreover, overexpression of the glycoprotein p170 in the resistant cell line was detected by Western blot analysis. By cytotoxicity assays and time-course experiments, different treatment schedules with resistance modulators (including clomipramine as reference drug) and doxorubicin were taken into account. The 16 h exposure of cells to 1 μM of modulator before doxorubicin demonstrated to be superior in sensitizing the resistant cell line. In particular, compounds 8, 7, 10, and 4 increasingly potentiated doxorubicin cytotoxicity, up to 5.6-fold in A2780-DX3 cells. The present results suggest promising indications for further development of these compounds as chemosensitizing drugs.

Original languageEnglish
Pages (from-to)413-420
Number of pages8
JournalInvestigational New Drugs
Volume21
Issue number4
DOIs
Publication statusPublished - Nov 2003

Keywords

  • Chemosensitizers
  • Cytotoxicity
  • Iminodibenzyl derivatives
  • Ovarian cancer cells
  • Phenothiazine derivatives
  • Quinolizidinyl derivatives

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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