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.

Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response

“…The enhanced expression of VEGF and IL-6 in MCF-7 cells treated with nilotinib is in contrast to findings in literature where inhibitory effects of nilotinib and imatinib on tumor cells are described [35] , [36] , [37] , [38] . However, these studies were predominantly performed with higher doses of nilotinib than the concentrations that we used for MCF-7 treatment.…”

Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo

“…IC-50s at 24, 48, and 72 hours were 53.85 ± 3.6, 22.85 ± 3, and 15.98 ± 2.6 for Ishikawa cells and 96.49 ± 9, 56.48 ± 5, and 30.08 ± 3.4 for HEC-1A cells respectively. The effect of IQ on Ishikawa and HEC-1A cells was also confirmed using sulforhodamine B colorimetric assay (Figure S1) (40). …”

Stathmin decreases cholangiocarcinoma cell line sensitivity to staurosporine-triggered apoptosis via the induction of ERK and Akt signaling

“…When Stathmin interference plasmids were transfected, RBE showed significantly decreased expression of p-Stathminand p-ERK, compared to RBE transfected with non-sense control, siRNA, even though the RBE cell was treated with Akt activator, dbcAMP [ 21 , 22 ](Figure 5E ). Furthermore, sorafenib [ 23 , 24 ], an inhibitor of protein kinase, is likely to aggravate the downregulated expression of p-ERK and p-Akt when Stathmin is knocked down (Figure 5F ). Then, TIC10 (an inhibition of Akt and ERK) was employed to precipitate the implication of ERK and AKT activity in Stathmin-regulated apoptosis.…”