Basic—Alimentary TractPhospho-Sulindac (OXT-328), a Novel Sulindac Derivative, Is Safe and Effective in Colon Cancer Prevention in Mice
Section snippets
Reagents and Cell Culture
P-S was synthesized as reported.6 Sulindac, A23187, and N-acetyl-L-cysteine (NAC) were from Sigma. Human colon cancer cell lines and the normal human colon cell line NCM460 were grown as monolayer as suggested by American Type Culture Collection (Manassas, VA). Cell growth was determined with the MTT assay (Promega, Madison, WI) following the manufacturer's instructions.7 Cells were treated with P-S with or without DFMO for ≤48 hours. Cell proliferation was assayed by 5-bromo-2′-deoxyuridine
P-S Inhibits the Growth of Cultured Colon Cancer Cells Through a Strong Cytokinetic Effect
To study the effect of P-S and sulindac on cell growth, we determined in various human colon cancer cells the 24-hour concentration values that inhibit their growth by 50% (IC50; Figure 1B). The IC50 values of P-S varied little among these cell lines (70–79.3 μmol/L), whereas those of sulindac were consistently >1000 μmol/L, indicating a potency enhancement of >14.2-fold.
We then elucidated the underlying cytokinetic effect of P-S on HT-29 and SW480 cells. P-S markedly reduced
Discussion
The successful pharmacologic agent against cancer must be effective and must lack significant side effects. Here, we demonstrate that P-S seems to meet both these requirements, markedly inhibiting intestinal tumors by itself and to a greater extent in combination with DFMO and appearing much safer than sulindac in preclinical studies.
P-S is a potent inhibitor of colon cancer cell lines (>14-fold more potent than sulindac) and exerts a profound inhibitory effect in preclinical models of colon
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Conflicts of interest The authors disclose no conflicts, except for B.R., who has an equity position in Medicon, Inc.
Funding This study was supported by grant R01-CA139453; N01-CN-43302 WA#7.