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Bipyraloxifene - a modified raloxifene vector against triple-negative breast cancer
Aleksandr Kazimir1, Tom Götze1, Blagoje Murganić2
1Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Leipzig University Johannisallee 29 04103 Leipzig Germany hey@uni-leipzig.de.
Abstract:
Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2'-bipyridine (2,2'-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-[4-(2,2'-bipyridin-4'-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells.
Insights
A new raloxifene-based molecule, bipyraloxifene, shows enhanced effectiveness against aggressive triple-negative breast cancer cells. It utilizes a caspase-mediated apoptosis pathway, offering improved activity and selectivity over raloxifene.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Selective oestrogen receptor modulators (SERMs) like raloxifene are used for oestrogen receptor-positive (ER+) breast cancer.
- Raloxifene shows some efficacy against triple-negative breast cancer (TNBC), suggesting ER-independent mechanisms.
- Developing novel compounds to target aggressive breast cancer subtypes is crucial.
Purpose of the Study:
- To synthesize and evaluate a novel raloxifene-metal chelator hybrid molecule, bipyraloxifene.
- To investigate the cytotoxic activity and mechanism of action of bipyraloxifene against various cancer cell lines, including TNBC.
- To compare the efficacy and selectivity of bipyraloxifene with raloxifene.
Main Methods:
- Synthetic modification of raloxifene by incorporating a 2,2'-bipyridine moiety to create bipyraloxifene.
- Assessment of cytotoxic activity against ER+ breast cancer, glioblastoma, and TNBC cell lines.
- Elucidation of the mechanism of action against TNBC, focusing on apoptosis pathways.
Main Results:
- Bipyraloxifene demonstrated significantly higher cytotoxic activity and selectivity compared to raloxifene.
- The enhanced activity was particularly notable against triple-negative stem-like MDA-MB-231 cells.
- Bipyraloxifene's mechanism of action against TNBC involves caspase-mediated apoptosis.
Conclusions:
- Bipyraloxifene represents a promising advancement in targeting aggressive breast cancers, including TNBC.
- The hybrid molecule offers improved potency and selectivity through ER-independent pathways.
- Further research into bipyraloxifene could lead to novel therapeutic strategies for challenging cancer types.
