Abstract
An adamantane derivative, 2, 2-Bis (4-(4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Our previous study showed that DPA inhibited the growth of human colon cancer cell Colo 205 xenografts. DPA-treated cells were arrested at G(0)/G(1), and the DPA-induced cell growth inhibition was irreversible after removal of DPA. Moreover, no acute toxicity was observed after an intra-peritoneal challenge of DPA in nude mice weekly. In this study, we examined the in vivo therapeutic potential of DPA combined with clinical chemotherapeutic agent CPT-11 in Colo 205 cell xenografts. The in vitro cytostatic and differentiative effects of DPA on human colon cancer cells was also evaluated. DPA exerted growth inhibitory activities in vitro against three human colon cancer cell lines (Colo 205, HT-29, and HCT-15). DPA-treated cells showed a more adhesive epithelial phenotype. The differentiation markers of carcinoembryonic antigen (CEA) and fibronectin (FN) were significantly increased in colon cancer cells after treatment with DPA. Further studies showed the induction of p21/Cip1, p27/Kip1, E-cadherin and dephosphorylated p120ctn expression was involved in DPA-induced anticancer effects. Interestingly, DPA-induced elevation of p21/Cip1 was independent of the induction of p53 in Colo 205 cells. in vivo results demonstrated that DPA enhanced the in vivo anticancer activity of the chemotherapeutic agent, CPT-11, by elevation of p53-independent p21/Cip1 and p27/Kip1 expression. Our results suggest that DPA appears to be a new potentially less toxic modality of cancer combinatory therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adamantane / administration & dosage
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Adamantane / analogs & derivatives
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Blotting, Western
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Cadherins / genetics
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Cadherins / metabolism
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives
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Carcinoembryonic Antigen / biosynthesis
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Catenins
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Cell Adhesion Molecules / metabolism
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Shape / drug effects
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Cell Shape / genetics
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Cell Survival / drug effects
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27
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Delta Catenin
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Dose-Response Relationship, Drug
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Drug Synergism
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Fibronectins / biosynthesis
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G1 Phase / drug effects
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HT29 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Irinotecan
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Male
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Mice
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Mice, Inbred ICR
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Mice, Nude
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Phosphoproteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Resting Phase, Cell Cycle / drug effects
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays / methods*
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beta Catenin / genetics
Substances
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2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane
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CDKN1A protein, human
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CDKN1B protein, human
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Cadherins
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Carcinoembryonic Antigen
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Catenins
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Cell Adhesion Molecules
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Cyclin-Dependent Kinase Inhibitor p21
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Fibronectins
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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beta Catenin
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Cyclin-Dependent Kinase Inhibitor p27
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Irinotecan
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Adamantane
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Camptothecin
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Delta Catenin