Time-lapse live cell imaging and flow analysis of multidrug resistance reversal by verapamil in bladder cancer cell lines.
OBJECTIVE
To examine the effects of verapamil on the intracellular drug pharmacokinetics of epirubicin using alternative dosing schedules. The results might inform the choices for optimizing clinical chemotherapy.


METHODS
Sensitive parental (MGH-U1) and multidrug resistant (MDR) (MGH-U1R and MGH-U1-MMC) bladder cancer cell lines were used. Fluorescence time-lapsed studies were performed on cells incubated with epirubicin alone or combined with verapamil. Flow cytometry was performed after the alternative dosing regimens.


RESULTS
Verapamil reversed the epirubicin localization patterns in MDR cells. Time-lapse imaging showed that nuclear epirubicin accumulation in MDR cells with verapamil followed the parental curve. The maximal reversal took >60 minutes. Flow cytometry showed increased epirubicin uptake in MDR cells co-incubated with verapamil. Preincubation was not as effective as co-incubation.


CONCLUSIONS
The results of our model indicate that longer exposure to MDR-class drugs, exemplified by epirubicin, increases uptake and the MDR reversing action of co-treatment with verapamil. The present results highlight the need for additional clinical trials of drug dosing and scheduling for combination intravesical chemotherapy regimens.
Featherstone
Jonathan M
JM
Department of Urology, Southampton University Hospitals, National Health Service Trust, United Kingdom.
Lwaleed
Bashir A
BA
Speers
Alan G
AG
Hayes
Matthew C
MC
Birch
Brian R
BR
Cooper
Alan J
AJ
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D014700:Verapamil