Naringenin enhances antitumor effect of doxorubicin by selective modulating drug efflux pathways. Naringenin will be a useful adjunct to improve the effectiveness of chemotherapeutic agents in treatment of human cancers.

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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.

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The metastasis of tumor cells is one of the major obstacles to successful clinical chemotherapy, surgery, and radiotherapy. Accordingly, new therapeutic strategies are needed for overcoming the occurrence of invasion and metastasis of tumor to improve patients' prognosis and survival.The anticoagulants low-molecular weight heparin (LMWH) and recombinant hirudin have shown anti-invasion and antimetastasis effects in experimental models.1,2) However, recombinant hirudin was found ineffective at preventing metastasis of HT168-M1 human melanoma cells in preclinical study, 1) suggesting that the anti-invasion and anti-metastasis effects of anticoagulants may vary by tumor cells. Most likely, each anticoagulant agent has its own mechanisms for application.The association of thrombosis and cancers as evidenced by platelet and fibrin deposition is well established.3-6) Previous studies indicate that exogenous thrombin (1 U/ml) acting through its protease-activated receptor (PAR-1) is capable of enhancing tumor adhesion to platelets, 7-9) endothelial cells, 10) fibronectin, and von Willebrand factor 8) in vitro. Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 11) and in vivo 7,8,12) as well as metastasis in experimental animals (via tail-vein injection of cancer cells). 9,13) The endogenous generation of host thrombin plays a significant role during tumor growth and spontaneous metastasis.2) Recent investigation demonstrated that advanced cancer is associated with a hypercoagulable state triggered by tissue factor (TF).14) TF-initiated thrombin generation is a critical step for metastasis through fibrin, platelet deposition, and PAR-1 signaling responses. In addition, PAR-2, which was not cleaved by thrombin, appears to be a cosignal with PAR-1 to elicit thrombin effects in metastatic tumor cells. 14)Hirudin is a highly potent and specific inhibitor of thrombin. It has shown an inhibitory effects against tumor growth and metastasis in experimental tumor models. [15][16][17] Hirudin induced a pronounced lag time in the appearance of tumor growth, as compared with phosphate-buffered saline (PBS) as control, but had no effect on existing tumor cells. We postulated that hirudin may have different effects on tumor growth depending on its administrations, because hirudin resulted in central necrosis of the tumor nodule, and inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs following administration at early stage of tumor cell inoculation in experimental animals. 2)Heparins are negatively charged polysaccharides that are able to bind to a number of proteins and molecules, thus probably influencing their biological activity. LMWH is composed of low-molecular weight fragments of heparin manufactured by controlled enzymatic or chemical depolymerization. LMWH may affect the progression of tumor in many ways. For example, it may potentially inhibit intravascular arrest and metastasis due to its anticoagulant role. [18][19][20] I...