Digital cell image analysis of verapamil-induced effects in chemosensitive and chemoresistant neoplastic cell lines.
We used chemosensitive and chemoresistant variants of the neoplastic mouse MXT mammary and human J82 and T24 bladder cell lines to characterize verapamil-induced cell proliferation and morphonuclear modifications in drug-treated and untreated cells. Chemoresistance to vinorelbine (Navelbine, a Vinca alkaloid derivative), to DIAM3 (an investigational alkylating compound) and to Adriamycin (an intercalating agent) in the presence or absence of verapamil was monitored by means of the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed that verapamil restored a significant level of chemosensitivity in doses such as 1 microM or 10 microM in the three chemoresistant variants. The digital cell image analysis of Feulgen-stained T24-resistant cell nuclei revealed that verapamil restored the drug-treated cell kinetics and morphonuclear features observed in the sensitive counterpart especially with respect to the effects of Adriamycin. Interestingly, verapamil induced a highly significant chromatin decondensation in resistant but not in sensitive variants. Such verapamil-induced decondensation may favour the accessibility of drugs to their DNA targets. Therefore, in addition to the well-known action of the drug on the influx of a cytotoxic compound from the cellular to the intracellular compartment, verapamil might also favour the accessibility of the nucleus, to the drug.
Etiévant
C
C
Division de Cancérologie Expérimentale I, Centre de Recherche Pierre Fabre, Castres, France.
Pauwels
O
O
Kiss
R
R
D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014700:Verapamil / Q000494:pharmacology*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D001388:Aziridines; D003959:Diamines; D009943:Organophosphorus Compounds; D014747:Vinblastine; D004317:Doxorubicin; C064571:DIAM 3; D014700:Verapamil; D000077235:Vinorelbine