The imidazole-mesalamine Schiff base Ru (II) complexes II39a–b were effective in inhibiting the growth of 3D colon cancer stem cell spheroids and bulk colon cancer cells at lower doses than salicycin and oxaliplatin, which were more resistant to the efflux of different transporters than oxaliplatin and did not enhance the expression of stem-regulatory genes (SOX2, KLF4, and OCT4). The gene discussed is KLF4; the disease is colonic neoplasm.