The novel heterocyclic trioxirane [(1,3,5-tris oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] exhibits a better anticancer effect than platinum-based chemotherapy by induction of apoptosis and curcumin further enhances its chemosensitivity.

Abstract

The heterocyclic trioxirane compound [1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] is a synthetic compound which has been used as an experimental anticancer agent in human clinical trials. Curcumin, an active natural compound in turmeric and curry, is an ingredient commonly used in the traditional diet of many Asian countries. In the present study, we observed that TATT exhibited a better anticancer effect on chemoresistant human colorectal cancer HT-29 cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with FDA-approved anticancer drugs (cisplatin, carboplatin, or oxaliplatin) using MTT assay. TATT also induced a stronger apoptotic effect than that seen with the three studied anticancer drugs, as characterized by externalization of phosphatidylserine using flow cytometry. Administration of caspase 8-specific inhibitor (z-IETD-fmk) and mitochondrial permeability transition pore inhibitor (cyclosporin A) demonstrated that TATT-induced apoptosis proceeded via both extrinsic and intrinsic signaling pathways. It is noteworthy that coadministration of curcumin further significantly increased TATT-induced cytotoxicity, externalization of phosphatidylserine (representing early apoptosis), and the percentages of cells at the sub-G1 phase (representing late apoptosis), producing an additivity and/or synergistic effect, and vice versa. Suppression of nuclear NF-κB was involved in curcumin-enhanced chemosensitivity of TATT. Overall, our data indicate that TATT exerts a chemotherapeutic effect on colorectal cancer cells and coadministration of curcumin enhances the treatment effect of TATT.

• Authors: Chun-Li Su, Ying-Ti Wang, Mu-Hsin Chang, Kang Fang, Kwunmin Chen
• Journal: Cell biochemistry and biophysics (Cell Biochem Biophys) Vol. 68 Issue 3 Pg. 597-609 (Apr 2014) ISSN: 1559-0283 [Electronic] United States
• PMID: 24078402 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione
• Antineoplastic Agents
• Epoxy Compounds
• NF-kappa B
• Organoplatinum Compounds
• Triazines
• Curcumin

Topics

• Antineoplastic Agents (adverse effects, chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Curcumin (pharmacology)
• Drug Approval
• Drug Synergism
• Epoxy Compounds (adverse effects, chemical synthesis, chemistry, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HT29 Cells
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Mitochondria (drug effects)
• NF-kappa B (metabolism)
• Organoplatinum Compounds (pharmacology)
• Triazines (adverse effects, chemical synthesis, chemistry, pharmacology)