ABSTRACT
BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.
Subject(s)
Apoptosis , Artemisinins , Colonic Neoplasms , G1 Phase Cell Cycle Checkpoints , Humans , Artemisinins/pharmacology , Artemisinins/chemistry , Apoptosis/drug effects , Colonic Neoplasms/pathology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/immunology , G1 Phase Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Adaptive Immunity/drug effects , Ruthenium/chemistry , Ruthenium/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , HCT116 Cells , HT29 Cells , Animals , Cytokines/metabolism , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , MiceABSTRACT
Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States, and chronic gut inflammation is a risk factor for CRC initiation and development. Curcuma longa L., or turmeric, has become one of the most studied herbal medicines in recent years due to its anticancer potentials. It is generally accepted that the major component in turmeric is curcuminoids, and the active constituent in curcuminoids is curcumin. However, unprocessed curcumin is characterized by poor water solubility, which means low bioavailability in humans. To increase the bioavailability of curcumin, in this study, we utilized a novel surfactant-formulated curcumin (CuminUP60[Formula: see text]) and evaluated its CRC chemopreventive activities. Compared with the chemo-sensitive CRC cell line HCT-116, the management of the CRC SW-480 cell line is a challenge, since the latter is chemo-resistant. In other words, these cancer cells resist the effects of the chemotherapy. Using the newly formulated CuminUP60[Formula: see text] water solution, this study demonstrated its strong antiproliferative effects on the SW-480 cells in a dose- and time-dependent manner. This new formulation induced early apoptosis and arrested the cell cycle in the G2/M phase via the upregulation of cyclin B1. We also observed that this new formulation possessed inhibitory effects on Th17 cell differentiation, which regulates the body's immune response against gut malignancies. In summary, our results exhibited a potential clinical utility of the surfactant-formulated curcumin in chemo-resistant colorectal cancer management.
