In vitro treatment with retinoids decreases bcl-2 protein expression and enhances dexamethasone-induced cytotoxicity and apoptosis in multiple myeloma cells

Patrizia Tosi, Annalisa Pellacani, Giuseppe Visani, Emanuela Ottaviani, Sonia Ronconi, Elena Zamagni, Monica Benni, Michele Cavo, Sante Tura

Research output: Contribution to journalArticle

Abstract

All-trans retinoic acid (ATRA) has been shown to inhibit in vitro growth of multiple myeloma (MM) cells, and this effect can be further potentiated by the addition of Dexamethasone (DEX). We here extended this study by testing the activity of 9-cis retinoic acid (9-cis RA) and 13-cis retinoic acid (13- cis RA), both alone and in combination with DEX, in two MM cell lines, U266 and RPM18226. Furthermore, we aimed at investigating the mechanisms involved in the interactions of retinoids and DEX in this setting. 9-cis RA appeared to be the most active agent in U266 cell line (IC(50) = 1.2 μmol/l vs 10.5 and 9.8 μmol/l obtained with ATRA and 13-cis RA, respectively) while, in RPMI 8226 cell line, 9-cis RA and 13-cis RA were almost equally cytotoxic (IC(50)= 1 and 0.8 μmol/l) and ATRA was less effective. Co-incubation with DEX resulted in a synergistic cytotoxic activity in both the cell lines except for the combinations DEX+9-cis RA in U266 cell line and DEX+ 13-cis RA in RPMI 8226 cell line, where the effect was merely additive. A synergistic cytotoxic effect of retinoids and DEX was also observed on fresh MM cells obtained from 7 patients. Both retinoids and DEX are known to be inducers of apoptosis; we verified that the combined inhibitory activity of retinoids and DEX could be attributed to an increased induction of apoptosis. This effect may be mediated by a reduced intracellular expression of BCL-2 protein, which indeed observed after prolonged in vitro treatment with retinoids. It has been described recently that an enhanced expression of BCL-2 protein can contribute to the occurrence of early chemoresistance; the downregulation of BCL-2 protein induced by retinoids could thus be exploited, by means of novel chemotherapy plus retinoids combinations, in order to improve the efficacy of conventional chemotherapy in MM.

Original languageEnglish
Pages (from-to)143-148
Number of pages6
JournalEuropean Journal of Haematology
Volume62
Issue number3
Publication statusPublished - 1999

Keywords

  • Apoptosis
  • BCL-2
  • Dexamethasone
  • Multiple myeloma
  • Retinoids

ASJC Scopus subject areas

  • Hematology

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