A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

Abstract

Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.

Keywords:

• sorafenib
• nilotinib
• castrate-resistant prostate cancer
• tyrosine kinase inhibitors
• nanomedicine

Supplementary materials

Figure S1 Quantification of Western blot.

Notes: Proteins of interest were normalized to β-tubulin and expressed as percentage of control. *P<0.05 compared to control, **P<0.05 comparing free drug versus micellar treatments, and ***P<0.05 comparing of free drug versus combination treatments.

Abbreviations: VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; FAK, focal adhesion kinase; AR, androgen receptor; SMA, poly(styrene-co-maleic) acid.

Figure S2 Quantification of Western blot and zymograph.

Notes: MMP-9 activity and MMP-9 and ISM-1 expression were normalized to control and expressed as percentage of control. *P<0.05 compared to control, and **P<0.05 comparing free drug versus micellar treatments.

Abbreviations: SMA, poly(styrene-co-maleic) acid; MMP, matrix metalloproteinase; ISM-1, isthmin-1.

Disclosure

The authors report no conflicts of interest in this work.