In vivo and in vitro properties of STX2484: a novel non-steroidal anti-cancer compound active in taxane-resistant breast cancer

• Published in: British journal of cancer Vol. 111; no. 2; pp. 300 - 308
• Main Authors: Stengel, C, Newman, S P, Day, J M, Chander, S K, Jourdan, F L, Leese, M P, Ferrandis, E, Regis-Lydi, S, Potter, B V L, Reed, M J, Purohit, A, Foster, P A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-07-2014; Nature Publishing Group
• Subjects: 692/699/67/1059/2326; 692/699/67/1059/99; 692/699/67/1347; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer Research; Cell cycle; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Cell Line, Tumor; Cytotoxicity; Drug dosages; Drug Resistance; Epidemiology; Female; Growth factors; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Isoquinolines - pharmacology; Mammary gland diseases; MCF-7 Cells; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Paclitaxel - pharmacology; Sulfonic Acids - pharmacology; Toxicity; Translational Therapeutics; Tumors; Xenograft Model Antitumor Assays; United Kingdom > UK; tubulin; paclitaxel; breast cancer; taxane resistance; STX2484; Antineoplastic agent; Breast disease; Breast cancer; Malignant tumor; Properties; In vitro; Resistance; Mammary gland diseases; In vivo; Cancerology; Tubulin; Taxane derivatives; Paclitaxel; Antimitotic; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.188

Background:
STX2484 is a novel non-steroidal compound with potent anti-proliferative activity. These studies aimed to identify STX2484’s mechanism of action,
in vivo
efficacy and activity in taxane-resistant breast cancer models.
Methods:
Effects of STX2484 and paclitaxel on proliferation, cell cycle and apoptosis were assessed
in vitro
in drug-resistant (MCF-7
DOX
) and non-resistant cells (MCF-7
WT
). STX2484 efficacy in
β
III tubulin overexpression in MCF-7 cells was also determined. Anti-angiogenic activity was quantified
in vitro
by a co-culture model and
in vivo
using a Matrigel plug assay. An MDA-MB-231 xenograft model was used to determine STX2484 efficacy
in vivo
.
Results:
STX2484 is a tubulin disruptor, which induces p53 expression, Bcl2 phosphorylation, caspase-3 cleavage, cell cycle arrest and apoptosis. In addition, STX2484 is a potent anti-angiogenic agent
in vitro
and
in vivo
. In breast cancer xenografts, STX2484 (20 mg kg
−1
p.o.) suppressed tumour growth by 84% after 35 days of daily dosing, with limited toxicity. In contrast to paclitaxel, STX2484 efficacy was unchanged in two clinically relevant drug-resistant models.
Conclusions:
STX2484 is an orally bioavailable microtubule-disrupting agent with
in vivo
anti-angiogenic activity and excellent
in vivo
efficacy with no apparent toxicity. Crucially, STX2484 has superior efficacy to paclitaxel in models of clinical drug resistance.