Cytotoxic activity of the titanium alkoxide (OPy)(2)Ti(4AP)(2) against cancer colony forming cells

Abstract

A novel family of titanium alkoxides with two stable pyridinemethoxide moieties bound to a titanium metal center were synthesized and tested for cytotoxic activity on a variety of cancer cell lines using colony formation assays. One compound, (OPy)(2)Ti(4AP)(2), where OPy is NC(5)H(5)CH(2)O(-), and 4AP is 4-aminophenoxide ((-)OC(6)H(5)(NH(2))-4), demonstrated increased cytotoxicity in breast, colon, and pancreatic cancer cell lines at 100 nanomolar levels with only short exposures. Further, (OPy)(2)Ti(4AP)(2) had activity in colon and pancreatic cancer cell lines that are usually resistant to chemotherapy. This demonstrates that these titanium compounds may have a role in anti-cancer therapy, similar to platinum-based compounds, and the (OPy)(2)Ti(4AP)(2) compound specifically deserves further investigation as an anti-cancer agent in chemo-resistant solid tumors.

Fig. 1

The structure of (OPy)₂Ti(4AP)₂ (10). a Unit cell view of the 3-dimensional structure of (OPy)₂Ti(4AP)₂. The titanium is represented by green, oxygen by red, nitrogen by blue, and carbon by grey. Hydrogen atoms have been removed for clarity. b The Schematic structure of (OPy)₂Ti(4AP)₂

Fig. 2

The effect of (OPy)₂Ti(4AP)₂ on pancreatic cancer cell lines. a Panc1, b BxPC3, and c McCain’s nut. Indicated cell numbers were adhered to culture dishes, exposed to varying nM concentrations of compound for 4 h, then washed, and incubated for 10–14 days for colony formation. Each experiment was performed twice in triplicate, with standard error of the mean indicated. Colony survival was compared to the plating efficiency of cells treated with vehicle alone as a control. Statistical differences at the p <0.05 level using Student’s t test between test and control cells is indicated by a star

Fig. 3

The effect of (OPy)₂Ti(4AP)₂ on breast cancer cell lines. a T47D, b MFC7, c MCF10a, and d MDA-MB-231. Indicated cell numbers were adhered to culture dishes, exposed to varying nM concentrations of compound for 4 h, then washed, and incubated for 10–14 days for colony formation. Each experiment was performed twice in triplicate, with standard error of the mean indicated. Colony survival was compared to the plating efficiency of cells treated with vehicle alone as a control. Statistical differences at the p <0.05 level using Student’s t test between test and control cells is indicated by a star

Fig. 4

The effect of (OPy)₂Ti(4AP)₂ on colon cancer cell lines. a SW48, b CaCo2, c HT29 and d T84. Indicated cell numbers were adhered to culture dishes, exposed to varying nM concentrations of compound for 4 h, then washed, and incubated for 10–14 days for colony formation. Each experiment was performed twice in triplicate, with standard error of the mean indicated. Colony survival was compared to the plating efficiency of cells treated with vehicle alone as a control. Statistical differences at the p <0.05 level using Student’s t test between test and control cells is indicated by a star