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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)585-596
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number3
DOIs
Publication statusPublished - Aug 2010

Fingerprint

P-Glycoprotein
Microtubules
Cells
Apoptosis
Breast Neoplasms
HL-60 Cells
Pharmaceutical Preparations
Multiple Drug Resistance
Neoplasms
ATP-Binding Cassette Transporters
Tumors
Proteins
Substrates
Cell Line
Oncology
Cell proliferation
Substrate Specificity
Cell Cycle
Leukemia
Binding Sites

Keywords

  • BCRP
  • Microtubule-targeting agents
  • Multi-drug resistance (MDR)
  • P-glycoprotein
  • PBOX

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells. / Nathwani, Seema Maria; Butler, Stephen; Fayne, Darren; McGovern, Naomi N.; Sarkadi, B.; Meegan, Mary J.; Lloyd, David G.; Campiani, Giuseppe; Lawler, Mark; Williams, D. Clive; Zisterer, Daniela M.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 3, 08.2010, p. 585-596.

Research output: Contribution to journalArticle

Nathwani, SM, Butler, S, Fayne, D, McGovern, NN, Sarkadi, B, Meegan, MJ, Lloyd, DG, Campiani, G, Lawler, M, Williams, DC & Zisterer, DM 2010, 'Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells', Cancer Chemotherapy and Pharmacology, vol. 66, no. 3, pp. 585-596. https://doi.org/10.1007/s00280-009-1200-9
Nathwani, Seema Maria ; Butler, Stephen ; Fayne, Darren ; McGovern, Naomi N. ; Sarkadi, B. ; Meegan, Mary J. ; Lloyd, David G. ; Campiani, Giuseppe ; Lawler, Mark ; Williams, D. Clive ; Zisterer, Daniela M. / Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 3. pp. 585-596.
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