Application of functional vincristine plus dasatinib liposomes to deletion of vasculogenic mimicry channels in triple-negative breast cancer

Abstract

Standard chemotherapy cannot eradicate triple-negative breast cancer (TNBC) while the residual cancer cells readily form the vasculogenic mimicry (VM) channels, which lead to the relapse of cancer after treatment. In this study, the functional vincristine plus dasatinib liposomes, modified by a targeting molecule DSPE-PEG2000-c(RGDyK), were fabricated to address this issue. The investigations were performed on TNBC MDA-MB-231 cells and MDA-MB-231 xenografts in nude mice. The liposomes exhibited the superior performances in the following aspects: the enhancement of cellular uptake via targeted action; the induction of apoptosis via activation of caspase 8, 9, and 3, increased expression of Bax, decreased expression of Mcl-1, and generation of reactive oxygen species (ROS); and the deletion of VM channels via inhibitions on the VM channel indicators, which consisted of vascular endothelial-cadherin (VE-Cad), focal adhesion kinase (FAK), phosphatidylinositide 3-kinase (PI3K), and matrix metallopeptidases (MMP-2, and MMP-9). Furthermore, the liposomes displayed the prolonged circulation time in the blood, the increased accumulation in tumor tissue, and the improved therapeutic efficacy along with deletion of VM channels in the TNBC-bearing mice. In conclusion, the nanostructured functional drug-loaded liposomes may provide a promising strategy for the treatment of invasive TNBC along with deletion of VM channels.

An Overview of Vasculogenic Mimicry in Breast Cancer

“…In fact, an in vitro model using liposomes showed that both drugs can cause cell death and inhibition of vessel formation in MDA-MB-231 cells grown in matrigel. In addition, the use of these liposomes decreases the tumor volume of xenografts in nude mice (68). The authors also demonstrated that the use of liposomes for transporting compounds with different targets, such as epirubicin (a DNA intercalant) and celecoxib (a cyclooxygenase 2 inhibitor) are able to inhibit VM in breast cancer cells (69).…”

Efficacy in Treating Lung Metastasis of Invasive Breast Cancer with Functional Vincristine Plus Dasatinib Liposomes

“…Results showed that the breast cancer cells exhibited the greatest cell shrinkage and nuclear shrinkage after treatment with functional vincristine plus dasatinib liposomes as compared to the controls. As revealed in our previous study [22], the related mechanisms were associated with the activated caspases 8 and 9 in the upstream, followed by the activated caspase 3 in the downstream, resulting in a cascade of apoptotic reactions in cancer cells [32]. …”

“…It is known that the secreted MMP-2 and MMP-9 in cancer cells cause hydrolysis of the extracellular matrix, enabling cancer cells to break through the original site into circulation system and finally form the secondary metastatic sites [38]. After treatment with functional vincristine plus dasatinib liposomes, significant downregulation of MMP-2 and 9 could explain the mechanism of preventing the invasion of breast cancer cells [22]. …”

“…DSPE-PEG 2000 -c(RGDyK) conjugate and functional vincristine plus dasatinib liposomes were developed and characterized in our previous study [22]. Briefly, egg phosphatidylcholine, cholesterol, DSPE-PEG 2000 , DSPE-PEG 2000 -c(RGDyK) conjugate, and dasatinib were dissolved in chloroform and methanol (3:1, v/v) in a ratio of 66:26:2.5:3:3.5 (mol/mol) in a pear-shaped bottle.…”

Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

“…However, dasatinib treatment also exerts immunosuppressive effects (Blake, et al 2008; Fraser, et al 2009), which may offset the effects of anti-tumor immunity. More recently, a nanoparticle formulation of dasatinib has been utilized in combination with the anti-microtubule chemotherapy, vincristine, and results indicate 1) enhanced tumor cell uptake of dasatinib, 2) increased apoptosis, and 3) decreased vascular mimicry channels (Zeng, et al 2015). Whether or not nanoparticle delivery of anti-Src siRNA can recapitulate the effects of liposomal dasatinib is unclear.…”