Flunarizine as a modulator of doxorubicin resistance in human colon-adenocarcinoma cells

✍ Scribed by Rosella Silvestrini; Nadia Zaffaroni; Aurora Costa; Linda Orlandi; Raffaella Villa; Hans R. Hendriks

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: French
• Weight: 489 KB
• Volume: 55
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910550420

✦ Synopsis

Abstract

The potential of the calcium‐entry blocker flunarizine in modulating the cytotoxicity of doxorubicin was investigated in human colon‐adenocarcinoma cell lines sensitive to (LoVo) or with experimentally induced resistance (LoVo/DX) to doxorubicin. Exposure to 1 to 2 m̈g/ml flunarizine for intervals of up to 24 hr did not affect cell survival in either line. Simultaneous exposure to flunarizine and doxorubicin for 1 hr selectively enhanced doxorubicin activity in the resistant cell line and not in the sensitive cell line. In particular, the doxorubicin concentration able to reduce cell survival by 50% dropped to one third. Moreover, simultaneous exposure to flunarizine significantly increased intracellular doxorubicin accumulation, as evaluated by fluorescence spectrophotometry. Again, flow‐cytometric analysis showed hyperpolarization of the membrane in resistant cells, starting from 15 min of exposure to 2 m̈g/ml flunarizine. Finally, in LoVo/DX cells, which normally express gpl70, a 24‐hr treatment with flunarizine markedly reduced the immuno‐reactivity of cells with 2 monoclonal antibodies (MAb57 and MRK16) directed against different external epitopes of the glycoprotein. The results from our study indicate the ability of flunarizine to positively modulate doxorubicin‐resistance in human colon‐adenocarcinoma cells expressing the multidrug‐resistance phenotype.