Mechanisms of multidrug resistance in bladder cancer: the role of the nuclear membrane

Abstract

Multidrug resistance (MDR) describes the phenomenon whereby cancer cells
exposed to a single cytotoxic drug develop cross resistance to numerous other
structurally unrelated chemotherapeutics. The development of MDR is a major
cause of cancer chemotherapy treatment failure in all types of cancer.

Numerous mechanisms of MDR have been elucidated which include ATPbinding
cassette (ABC) transporter proteins, cytoplasmic vaults, alterations in
topoisomerase II and increased expression of glutathione-S-transferases, all of
which result in reduced chemotherapeutic efficacy.

Superficial bladder cancer is commonly treated with adjuvant intravesical
chemotherapy using mitomycin C or epirubicin (an anthracycline), following
surgical resection. However, despite this treatment, the recurrence rates of
these tumours can approach 60%. This high recurrence rate represents the
development of MDR in many cases.

Previous work using anthracycline fluorescence has shown that MDR cells
have reduced levels of anthracycline uptake and also demonstrate a
characteristic nuclear sparing of drug uptake. This nuclear sparing
phenomenon in MDR cells transcends tissue type and suggests that the
nuclear membrane may also play a role in MDR.

The work described herein discusses the current role of chemotherapy in the
treatment of superficial bladder cancer, mechanisms of MDR and the role of the
nuclear membrane in MDR. Following this our investigation of the role of the
nuclear membrane is described, using a number of novel techniques including
cell fusion and microinjection. In addition, we investigated MDR modulation by
verapamil, with analysis of changes in cellular, cytoplasmic and nuclear drug
uptake mediated by this known MDR reversing agent.

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Identifiers

ORCID for J. Primrose: orcid.org/0000-0002-2069-7605

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