Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells

Md Khalilur Rahman; Yassir Al-Zubaidi; Kirsi Bourget; Yongjuan Chen; Stanton Tam; Fanfan Zhou; Michael Murray

doi:10.1016/j.xphs.2022.06.009

Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells

J Pharm Sci. 2022 Aug;111(8):2180-2190. doi: 10.1016/j.xphs.2022.06.009. Epub 2022 Jun 11.

Authors

Md Khalilur Rahman¹, Yassir Al-Zubaidi², Kirsi Bourget¹, Yongjuan Chen², Stanton Tam², Fanfan Zhou³, Michael Murray⁴

Affiliations

¹ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences; Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia.
² Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences.
³ Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia.
⁴ Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences; Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia. Electronic address: michael.murray@sydney.edu.au.

PMID: 35700798
DOI: 10.1016/j.xphs.2022.06.009

Abstract

Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.

Keywords: Cancer chemotherapy; Cell culture; Drug resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Breast Neoplasms*
Cell Line, Tumor
Epothilones
Female
Humans
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Receptors, Vascular Endothelial Growth Factor / therapeutic use
Taxoids / pharmacology
Triple Negative Breast Neoplasms* / drug therapy
Vascular Endothelial Growth Factor A

Substances

Antineoplastic Agents
Epothilones
Poly(ADP-ribose) Polymerase Inhibitors
Taxoids
Vascular Endothelial Growth Factor A
Receptors, Vascular Endothelial Growth Factor
ixabepilone