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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2010

01-08-2010 | Original Article

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

Authors: Seema-Maria Nathwani, Stephen Butler, Darren Fayne, Naomi N. McGovern, Balazs Sarkadi, Mary J. Meegan, David G. Lloyd, Giuseppe Campiani, Mark Lawler, D. Clive Williams, Daniela M. Zisterer

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2010

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Abstract

Purpose

The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.

Methods

We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.

Results

We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.

Conclusion

Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.
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Metadata
Title
Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells
Authors
Seema-Maria Nathwani
Stephen Butler
Darren Fayne
Naomi N. McGovern
Balazs Sarkadi
Mary J. Meegan
David G. Lloyd
Giuseppe Campiani
Mark Lawler
D. Clive Williams
Daniela M. Zisterer
Publication date
01-08-2010
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-009-1200-9

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