Increased potency of the PHSCN dendrimer as an inhibitor of human prostate cancer cell invasion, extravasation, and lung colony formation

Abstract

Background Activated α5β1 integrin occurs specifically on tumor cells and on endothelial cells of tumor–associated vasculature, and plays a key role in invasion and metastasis. The PHSCN peptide (Ac-PHSCN-NH2) preferentially binds activated α5β1, to block invasion in vitro, and inhibit growth, metastasis and tumor recurrence in preclinical models of prostate cancer. In Phase I clinical trial, systemic Ac-PHSCN-NH2 monotherapy was well tolerated, and metastatic disease progression was prevented for 4–14 months in one third of treated patients. Results We have developed a significantly more potent derivative, the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP). Using in vitro invasion assays with naturally serum-free basement membranes, we observed that the PHSCN dendrimer was 130– to 1900–fold more potent than the PHSCN peptide at blocking α5β1–mediated invasion by DU 145 and PC-3 human prostate cancer cells, whether invasion was induced by serum, or by the Ac-PHSRN-NH2 peptide, under serum-free conditions. The PHSCN dendrimer was also approximately 800 times more effective than PHSCN peptide at preventing DU 145 and PC-3 extravasation in the lungs of athymic mice. Chou-Talalay analysis suggested that inhibition of both invasion in vitro and extravasation in vivo by the PHSCN dendrimer are highly synergistic. We found that many extravasated DU 145 and PC-3 cells go on to develop into metastatic colonies, and that a single pretreatment with the PHSCN dendrimer was 100–fold more affective than the PHSCN peptide at reducing lung colony formation. Conclusions Since many patients newly diagnosed with prostate cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy, like the PHSCN dendrimer, which prevents metastatic progression by inhibiting invasion, could be very beneficial.

Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

“…No side effects emerged or became worse with continued chronic dosing of ATN-161 [153]. Recently, PHSCN dendrimers were synthesized and shown to be more potent than the initial peptide for inhibiting α5β1 integrin-mediated MMP-1 secretion in vitro and for inhibiting human prostate cancer cell invasion, extravasion and lung metastasis in vivo [154]. Similar results were reported on human breast cancer cells [155].…”

RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis

“…Treatment started prior to the removal of DU145 tumours completely prevented recurrence of the primary tumour and significantly reduced metastasis [185]. A polylysine dendrimer, Ac-PHSCNGGK-MAP, bearing 8 PHSCN peptides has been shown to be significantly more potent than ATN-161, with synergistic enhancements of inhibition of fibronectin-induced invasion of PC-3 or DU145 cells in vitro , and inhibition of cell extravasation and development of micrometastases in the lungs in vivo [186] To date, studies on PHSCN peptides have focussed on combating lung metastasis. Investigation of PHSCN peptides effects on bone metastasis will be important in determining whether they will prove to be an effective general treatment for advanced disease.…”

Copper(II) coordination properties of the integrin ligand sequence PHSRN and its new β-cyclodextrin conjugates

“…It is also able to induce human microvascular endothelial cell invasion and initiating angiogenesis, while the single point mutated (Arg→Cys) PHSCN peptide, acts as a competitive inhibitor of PHSRN sequence [19]. The PHSCN is able to prevent metastatic progression in carcinoma prostate [20,21] and the combined use of PHSCN and the copper chelating agent tetrathiomolybdate, was more effective in reduce tumour growth at the primary and metastatic sites [22]. Noteworthy, copper metabolism is altered in human cancers with increased extracellular levels of metal [23].…”