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1.
PLoS One ; 9(8): e101708, 2014.
Article in English | MEDLINE | ID: mdl-25093583

ABSTRACT

Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.


Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/therapeutic use , Drug Approval , Drug Repositioning/methods , Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Animals , Benzimidazoles/therapeutic use , Biphenyl Compounds , Cell Line, Tumor , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Etidronic Acid/analogs & derivatives , Etidronic Acid/therapeutic use , Female , High-Throughput Screening Assays/methods , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Mice, Transgenic , Risedronic Acid , Temozolomide , Tetrazoles/therapeutic use
2.
Carcinogenesis ; 33(9): 1639-46, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22678114

ABSTRACT

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.


Subject(s)
Antineoplastic Agents/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Epithelial-Mesenchymal Transition , Pyrroles/pharmacology , Sulfonamides/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Dinoprostone/biosynthesis , Female , HT29 Cells , Humans , Mice , Mice, Nude , Vascular Endothelial Growth Factor A/physiology
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