NOSH-Aspirin Inhibits Colon Cancer Cell Growth: Effects Of Positional Isomerism.

BACKGROUND

NOSH-aspirin, a novel hybrid that releases nitric oxide (NO) and hydrogen sulfide (HS) was designed to overcome the potential side effects of aspirin.

AIM

We compared the cell growth inhibitory properties of ortho-, meta-, and para-NOSH-aspirins. Effects of electron donating/withdrawing groups on the stability and biological activity of these novel compounds were also evaluated.

METHODS

Cell line: HT-29 (Cyclooxygenase, COX-1 & -2 expressing) and HCT 15 (COX null) human colon adenocarcimoa; Cell growth: MTT; Cell cycle phase distribution: Flow cytometry; Apoptosis: subdiploid (sub-G/G) peak in DNA content histograms; Proliferation: PCNA; ROS: measured hydrogen peroxide and super oxide by flow cytometry using DCFDA and DHE dyes.

RESULTS

The ICs for growth inhibition in µM at 24h were, HT-29: ortho-NOSH-ASA (0.04±0.011), meta-NOSH-ASA (0.24±0.11), para-NOSH-ASA (0.46±0.17); significance between the groups were: o vs m P>0.05, o vs p P<0.05, m vs p P>0.05; HCT 15: ortho-NOSH-ASA (0.062±0.006), meta-NOSH-ASA (0.092±0.004), para-NOSH-ASA (0.37±0.04); significance between the groups were: o vs m P<0.01, o vs p P<0.001, m vs p P<0.001. Electron donating/withdrawing groups significantly affected these ICs. All positional isomers qualitatively had similar effects on proliferation, apoptosis, and caused G/G cell cycle arrest in both colon cancer cell lines. The underlying mechanism for these observations appeared to be mediated through ROS, as pretreatment of the cells with N-acetylcysteine, partially blocked these effects.

CONCLUSIONS

Positional isomerism affects the potency of NOSH-aspirin. The effects appear to be COX independent.