Abstract
Small molecule inhibitors against protein geranylgeranyltransferase-I such as P61A6 have been shown to inhibit proliferation of a variety of human cancer cells and exhibit antitumor activity in mouse models. Development of these inhibitors could be dramatically accelerated by conferring tumor targeting and controlled release capability. As a first step towards this goal, we have encapsulated P61A6 into a new type of liposomes that open and release cargos only under low pH condition. These low pH-release type liposomes were prepared by adjusting the ratio of two types of phospholipid derivatives. Loading of geranylgeranyltransferase-I inhibitor (GGTI) generated liposomes with average diameter of 50–100 nm. GGTI release in solution was sharply dependent on pH values, only showing release at pH lower than 6. Release of cargos in a pH-dependent manner inside the cell was demonstrated by the use of a proton pump inhibitor Bafilomycin A1 that Increased lysosomal pH and inhibited the release of a dye carried in the pH-liposome. Delivery of GGTI to human pancreatic cancer cells was demonstrated by the inhibition of protein geranylgeranylation inside the cell and this effect was blocked by Bafilomycin A1. In addition, GGTI delivered by pH-liposomes induced proliferation inhibition, G1 cell cycle arrest that is associated with the expression of cell cycle regulator p21CIP1/WAF1. Proliferation inhibition was also observed with various lung cancer cell lines. Availability of nanoformulated GGTI opens up the possibility to combine with other types of inhibitors. To demonstrate this point, we combined the liposomal-GGTI with farnesyltransferase inhibitor (FTI) to inhibit K-Ras signaling in pancreatic cancer cells. Our results show that the activated K-Ras signaling in these cells can be effectively inhibited and that synergistic effect of the two drugs is observed. Our results suggest a new direction in the use of GGTI for cancer therapy.
Highlights
A class of anticancer drugs intended to inhibit membrane association of signaling proteins have been developed over the years
We further extend the use of liposomal geranylgeranyltransferase-I inhibitor (GGTI) for cancer therapy by demonstrating that liposomal-GGTI can be combined with farnesyltransferase inhibitor (FTI) to inhibit K-Ras signaling in pancreatic cancer cells
We have previously shown that GGTI induces expression of a cell cycle regulator p21CIP1/ WAF1 [7]
Summary
A class of anticancer drugs intended to inhibit membrane association of signaling proteins have been developed over the years. By screening a chemical compound library constructed by phosphine catalysis of allenoate compounds, we previously identified several GGTase-I inhibitor (GGTI) compounds that block the protein modification and inhibit membrane association and function of Ral, Rho, and Rap subfamily proteins [8,9]. These compounds inhibit GGTase-I by competing with its substrate proteins. Efficacy of GGTI P61A6 to inhibit tumor growth was demonstrated using human pancreatic cancer xenograft [10]. A similar inhibition of tumor growth was observed by the use of lung cancer xenografts in mice [11]
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